Selective androgen receptor degrader (sard) ligands and methods of use thereof

ABSTRACT

This invention is directed to pyrrole, pyrazole, imidazole, triazole, and morpholine based selective androgen receptor degrader (SARD) compounds including heterocyclic anilide rings and their synthetic precursors, R-isomers, and non-hydroxylated and/or non-chiral propanamides, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy&#39;s disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part Application of U.S. patentapplication Ser. No. 15/923,668, filed on Mar. 16, 2018, which is aContinuation-in-Part Application of U.S. patent application Ser. No.15/620,761, filed on Jun. 12, 2017, which claims the benefit of U.S.Provisional Ser. No. 62/348,474, filed on Jun. 10, 2016, U.S.Provisional Ser. No. 62/455,397, filed on Feb. 6, 2017 and U.S.Provisional Ser. No. 62/482,036 filed on Apr. 5, 2017, which are allincorporated in their entirety herein by reference.

FIELD OF THE INVENTION

This invention is directed to pyrrole, pyrazole, imidazole, triazole,and morpholine based selective androgen receptor degrader (SARD)compounds including heterocyclic anilide rings and their syntheticprecursors, R-isomers, and non-hydroxylated and/or non-chiralpropanamides, and pharmaceutical compositions and uses thereof intreating hyperproliferations of the prostate including pre-malignanciesand benign prostatic hyperplasia, prostate cancer, advanced prostatecancer, castration resistant prostate cancer, triple negative breastcancer, other cancers expressing the androgen receptor, androgenicalopecia or other hyperandrogenic dermal diseases, Kennedy's disease,amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA),and uterine fibroids, and to methods for reducing the levels of androgenreceptor-full length (AR-FL) including pathogenic or resistancemutations, AR-splice variants (AR-SV), and pathogenic polyglutamine(polyQ) polymorphisms of AR in a subject.

BACKGROUND OF THE INVENTION

Prostate cancer (PCa) is one of the most frequently diagnosednoncutaneous cancers among men in the US and is the second most commoncause of cancer deaths with more than 200,000 new cases and over 30,000deaths each year in the United States. PCa therapeutics market isgrowing at an annual rate of 15-20% globally.

Androgen-deprivation therapy (ADT) is the standard of treatment foradvanced PCa. Patients with advanced prostate cancer undergo ADT, eitherby luteinizing hormone releasing hormone (LHRH) agonists, LHRHantagonists or by bilateral orchidectomy. Despite initial response toADT, disease progression is inevitable and the cancer emerges ascastration-resistant prostate cancer (CRPC). Up to 30% of patients withprostate cancer that undergo primary treatment by radiation or surgerywill develop metastatic disease within 10 years of the primarytreatment. Approximately 50,000 patients a year will develop metastaticdisease, which is termed metastatic CRPC (mCRPC).

Patients with CRPC have a median survival of 12-18 months. Thoughcastration-resistant, CRPC is still dependent on the androgen receptor(AR) signaling axis for continued growth. The primary reason for CRPCre-emergence is re-activation of AR by alternate mechanisms such as: 1)intracrine androgen synthesis, 2) AR splice variants (AR-SV), e.g., thatlack ligand binding domain (LBD), 3) AR-LBD mutations with potential toresist AR antagonists (i.e., mutants that are not sensitive toinhibition by AR antagonists, and in some cases AR antagonists act asagonists of the AR bearing these LBD mutations), and 4) amplificationsof the AR gene within the tumor. A critical barrier to progress intreating CRPC is that AR signaling inhibitors such as enzalutamide,bicalutamide, and abiraterone, acting through the LBD, fail to inhibitgrowth driven by the N-terminal domain (NTD)-dependent constitutivelyactive AR-SV such as AR-V7, the most prominent AR-SV. Recent high-impactclinical trials with enzalutamide and abiraterone in CRPC patientsdemonstrated that just 13.9% of AR-V7-positive patients among 202patients starting treatment with enzalutamide (Xtandi) or abirateroneacetate (Zytiga) had PSA responses to either of the treatments(Antonarakis E S, Lu C, Luber B, et al. J. Clin. Oncol. 2017 Apr. 6.doi: 10.1200/JCO.2016.70.1961), indicating the requirement for nextgeneration AR antagonists that target AR-SVs. In addition, a significantnumber of CRPC patients are becoming refractory to abiraterone orenzalutamide, emphasizing the need for next generation AR antagonists.

Current evidences demonstrate that CRPC growth is dependent onconstitutively active AR including AR-SV's that lack the LBD such asAR-V7 and therefore cannot be inhibited by conventional antagonists. ARinhibition and degradation through binding to a domain that is distinctfrom the AR LBD provides alternate strategies to manage CRPC.

Herein the NTD is biophysically characterized to interact with the SARDsof this invention via fluorescence polarization (FP) and NMR (Example9). Biochemical evidence also supports the SARDs of this inventionbinding to a domain other than the LBD. E.g., SARDs of this inventiondegrade AR-SV in D567es cells lacking the expression of any ARcontaining the LBD (Example 5). Further, the R- and S-isomers of theSARDs of this invention possess equipotent SARD activity despitedemonstrated differences in the binding and inhibition ofandrogen-dependent transactivation via the LBD (Examples 3 and 4). Thereport of SARD activity mediated through the NTD of AR is anunprecedented observation that may help explanation the prodigious ARantagonism profiles seen with the SARDs of this invention.

Molecules that degrade the AR prevent any inadvertent AR activationthrough growth factors or signaling pathways, or promiscuousligand-dependent activation. In addition, molecules that inhibit theconstitutive activation of AR-SVs are extremely important to provideextended benefit to CRPC patients.

Currently only a few chemotypes are known to degrade AR which includethe SARDs ARN-509, AZD-3514, and ASC-J9. However, these moleculesdegrade AR indirectly at much higher concentrations than their bindingcoefficient and they fail to degrade the AR-SVs that have become inrecent years the primary reason for resurgence of treatment-resistantCRPC.

This invention describes novel AR antagonists with unique pharmacologythat strongly (high potency and efficacy) and selectively bind AR(better than known antagonists in some cases; bind to LBD and/or NTD),antagonize AR, and degrade AR full length (AR-FL) and AR-SV. Selectiveandrogen receptor degrader (SARD) compounds possess dual degradation andAR-SV inhibitory functions and hence are distinct from any availableCRPC therapeutics. These novel selective androgen receptor degrader(SARD) compounds inhibit the growth of PCa cells and tumors that aredependent on AR-FL and AR-SV for proliferation.

SARDs have the potential to evolve as new therapeutics to treat CRPCsthat are untreatable with any other antagonists. This unique property ofdegrading AR-SV has extremely important health consequences for prostatecancer. Till date only one series of synthetic molecules (EPI-001,EPI-506, etc.) and some marine natural products such as the sinkotamidesand glycerol ether Naphetenone B, are reported to bind to AR-NTD andinhibit AR function and PCa cell growth, albeit at lower affinity andinability to degrade the receptor. The SARDs reported herein also bindto AR-NTD and inhibit NTD-driven (e.g., ligand independent) AR activity.

The positive correlation between AR and PCa and the lack of a fail-safeAR antagonist, emphasizes the need for molecules that inhibit ARfunction through novel or alternate mechanisms and/or binding sites, andthat can elicit antagonistic activities within an altered cellularenvironment.

Although traditional antiandrogens such as enzalutamide, bicalutamideand flutamide and androgen deprivation therapies (ADT) were approved foruse in prostate cancer, there is significant evidence that antiandrogenscould also be used in a variety of other hormone dependent and hormoneindependent cancers. For example, antiandrogens have been tested inbreast cancer (enzalutamide; Breast Cancer Res. (2014) 16(1): R7),non-small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9),partial androgen insensitivity syndrome (PAIS) associated malignanciessuch as gonadal tumors and seminoma, advanced pancreatic cancer (WorldJ. Gastroenterology 20(29), 9229), cancer of the ovary, fallopian tubes,or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38,724-731; ADT was tested in AR-expressing recurrent/metastatic salivarygland cancers and was confirmed to have benefit on progression freesurvival and overall survival endpoints), bladder cancer (Oncotarget6(30), 29860-29876); Int J. Endocrinol (2015), Article ID 384860),pancreatic cancer, lymphoma (including mantle cell), and hepatocellularcarcinoma. Use of a more potent antiandrogen such as a SARD in thesecancers may more efficaciously treat the progression of these and othercancers. Other cancers may also benefit from SARD treatment such asbreast cancer (e.g., triple negative breast cancer (TNBC)), testicularcancer, cancers associated with partial androgen insensitivity syndromes(PAIS) such as gonadal tumors and seminoma, uterine cancer, ovariancancer, cancer of the fallopian tubes or peritoneum, salivary glandcancer, bladder cancer, urogenital cancer, brain cancer, skin cancer,lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma,renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer,endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC),gastric cancer, colon cancer, perianal adenoma, or central nervoussystem cancer.

Triple negative breast cancer (TNBC) is a type of breast cancer lackingthe expression of the estrogen receptor (ER), progesterone receptor(PR), and HER2 receptor kinase. As such, TNBC lacks the hormone andkinase therapeutic targets used to treat other types of primary breastcancers. Correspondingly, chemotherapy is often the initialpharmacotherapy for TNBC. Interestingly, AR is often still expressed inTNBC and may offer a hormone targeted therapeutic alternative tochemotherapy. In ER-positive breast cancer, AR is a positive prognosticindicator as it is believed that activation of AR limits and/or opposesthe effects of the ER in breast tissue and tumors. However, in theabsence of ER, it is possible that AR actually supports the growth ofbreast cancer tumors. Though the role of AR is not fully understood inTNBC, we have evidence that certain TNBC's may be supported by androgenindependent activation of AR-SVs lacking the LBD or androgen-dependentactivation of AR full length. As such, enzalutamide and otherLBD-directed traditional AR antagonists would not be able to antagonizeAR-SVs in these TNBC's. However, SARDs of this invention which arecapable of destroying AR-SVs (see Table 1 and Example 5) through abinding site in the NTD of AR (see Example 9) would be able toantagonize AR including AR-SV observed in TNBC patient derivedxenografts and provide an anti-tumor effect, as shown in Example 8.

Traditional antiandrogens such as bicalutamide and flutamide wereapproved for use in prostate cancer. Subsequent studies havedemonstrated the utility of antiandrogens (e.g., flutamide,spironolactone, cyproterone acetate, finasteride and chlormadinoneacetate) in androgen-dependent dermatological conditions such asandrogenic alopecia (male pattern baldness), acne vulgaris, andhirsutism (e.g., in female facial hair). Prepubertal castration preventssebum production and androgenic alopecia but this can be reversed by useof testosterone, suggesting its androgen-dependence.

The AR gene has a polymorphism of glutamine repeats (polyQ) within exon1 which when shortened may augment AR transactivation (i.e.,hyperandrogenism). It has been found that shortened polyQ polymorphismsare more common in people with alopecia, hirsutism, and acne. Classicantiandrogens are undesirable for these purposes because they areineffective through dermal dosing and their long-term systemic useraises the risks of untoward sexual effects such as gynecomastia andimpotence. Further, similar to CPRC discussed above, inhibition ofligand-dependent AR activity alone may not be sufficient as AR can beactivated by various cellular factors other than the endogeneousandrogens testosterone (T) and dihydrotestosterone (DHT), such as growthfactors, kinases, co-activator overexpression and/or promiscuousactivation by other hormones (e.g., estrogens or glucocorticoids).Consequently, blocking the binding of T and DHT to AR with a classicalantiandrogen may not be sufficient to have the desired efficacy.

An emerging concept is the topical application of a SARD to destroy theAR locally to the affected areas of the skin or other tissue withoutexerting any systemic antiandrogenism. For this use, a SARD that doesnot penetrate the skin or is rapidly metabolized would be preferable.

Supporting this approach is the observation that cutaneous wound healinghas been demonstrated to be suppressed by androgens. Castration of miceaccelerates cutaneous wound healing while attenuating the inflammationin the wounds. The negative correlation between androgen levels andcutaneous healing and inflammation, in part, explains another mechanismby which high levels of endogenous androgens exacerbate hyperandrogenicdermatological conditions. Further, it provides a rationale for thetreatment of wounds such as diabetic ulcers or even trauma, or skindisorders with an inflammatory component such as acne or psoriasis, witha topical SARD.

Androgenic alopecia occurs in ˜50% of Caucasian males by midlife and upto 90% by 80 years old. Minoxidil (a topical vasodilator) andfinasteride (a systemic 5 alpha reductase type II inhibitor) are FDAapproved for alopecia but require 4-12 months of treatment to produce atherapeutic effect and only arrest hair loss in most with mild tomoderate hair regrowth in 30-60%. Since currently available treatmentshave slow and limited efficacy that varies widely between individuals,and produce unwanted sexual side effects, it is important to find anovel approach to treat androgenic alopecia and other hyperandrogenicdermatologic diseases.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative diseasecharacterized by selective loss of upper and lower motor neurons andskeletal muscle atrophy. Epidemiologic and experimental evidence suggestthe involvement of androgens in ALS pathogenesis (“Anabolic/androgenicsteroid nandrolone exacerbates gene expression modifications induced bymutant SOD1 in muscles of mice models of amyotrophic lateral sclerosis.”Galbiati M, Onesto E, Zito A, Crippa V, Rusmini P, Mariotti R,Bentivoglio M, Bendotti C, Poletti A. Pharmacol. Res. 2012, 65(2),221-230), but the mechanism through which androgens modify the ALSphenotype is unknown. A transgenic animal model of ALS demonstratedimproved survival upon surgical castration (i.e., androgen ablation).Treatment of these castrated animals with the androgen agonistnandrolone decanoate worsened disease manifestations. Castration reducesthe AR level, which may be the reason for extended survival. Thesurvival benefit is reversed by androgen agonist (“Androgens affectmuscle, motor neuron, and survival in a mouse model of SOD1-relatedamyotrophic lateral sclerosis.” Aggarwal T, Polanco M J, Scaramuzzino C,Rocchi A, Milioto C, Emionite L, Ognio E, Sambataro F, Galbiati M,Poletti A, Pennuto M. Neurobiol. Aging. 2014 35(8), 1929-1938). Notably,stimulation with nandrolone decanoate promoted the recruitment ofendogenous androgen receptor into biochemical complexes that wereinsoluble in sodium dodecyl sulfate, a finding consistent with proteinaggregation. Overall, these results shed light on the role of androgensas modifiers of ALS pathogenesis via dysregulation of androgen receptorhomeostasis. Antiandrogens should block the effects of nandroloneundecanoate or endogeneous androgens and reverse the toxicities due toAR aggregation. Further, an antiandrogen that can block action ofLBD-dependent AR agonists and concomitantly lower AR protein levels,such as the SARDs of this invention, would be therapeutic in ALS.Riluzole is an available drug for ALS treatment, however, it onlyprovides short-term effects. There is an urgent need for drugs thatextend the survival of ALS patients.

Androgen receptor action promotes uterine proliferation.Hyperandrogenicity of the short polyQ AR has been associated withincreased leiomyoma or uterine fibroids. (Hsieh Y Y, Chang C C, Tsai FJ, Lin C C, Yeh L S, Peng C T. J. Assist. Reprod. Genet. 2004, 21(12),453-457). A separate study of Brazilian women found that shorter andlonger [CAG](n) repeat alleles of AR were exclusive to the leiomyomagroup in their study (Rosa F E, Canevari Rde A, Ambrosio E P, RamosCirilo P D, Pontes A, Rainho C A, Rogatto S R. Clin. Chem. Lab. Med.2008, 46(6), 814-823). Similarly, in Asian Indian women long polyQ ARwas associated with endometriosis and leiomyoma and can be regarded ashigh-risk markers. SARDs could be used in women with uterine fibroids,especially those expressing shorter and longer [CAG](n) repeat alleles,to treat existing uterine fibroids, prevent worsening of fibroids and/orameliorate carcinogenicity associated with fibroids.

An abdominal aortic aneurysm (AAA) is an enlarged area in the lower partof the aorta, the major blood vessel that supplies blood to the body.The aorta, about the thickness of a garden hose, runs from your heartthrough the center of your chest and abdomen. Because the aorta is thebody's main supplier of blood, a ruptured abdominal aortic aneurysm cancause life-threatening bleeding. Depending on the size and the rate atwhich your abdominal aortic aneurysm is growing, treatment may vary fromwatchful waiting to emergency surgery. Once an abdominal aortic aneurysmis found, doctors will closely monitor it so that surgery can be plannedif it is necessary. Emergency surgery for a ruptured abdominal aorticaneurysm can be risky. AR blockade (pharmacologic or genetic) reducesAAA. Davis et al. (Davis J P, Salmon M, Pope N H, Lu G, Su G, Meher A,Ailawadi G, Upchurch G R Jr. J Vasc Surg (2016) 63(6):1602-1612) showedthat flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated porcinepancreatic elastase (0.35 U/mL) induced AAA by 84.2% and 91.5% comparedto vehicle (121%). Further AR −/−mice showed attenuated AAA growth(64.4%) compared to wildtype (both treated with elastase).Correspondingly, administration of a SARD to a patient suffering from anAAA may help reverse, treat or delay progression of AAA to the pointwhere surgery is needed.

X-linked spinal-bulbar muscular atrophy (SBMA—also known as Kennedy'sdisease) is a muscular atrophy that arises from a defect in the androgenreceptor gene on the X chromosome.

Proximal limb and bulbar muscle weakness results in physical limitationsincluding dependence on a wheelchair in some cases. The mutation resultsin a protracted polyglutamine tract added to the N-terminal domain ofthe androgen receptor (polyQ AR). Binding and activation of thislengthened polyQ AR by endogeneous androgens (testosterone and DHT)results in unfolding and nuclear translocation of the mutant androgenreceptor. The androgen-induced toxicity and androgen-dependent nuclearaccumulation of polyQ AR protein seems to be central to thepathogenesis. Therefore, the inhibition of the androgen-activated polyQAR might be a therapeutic option (A. Baniahmad. Inhibition of theandrogen receptor by antiandrogens in spinobulbar muscle atrophy. J.Mol. Neurosci. 2016 58(3), 343-347). These steps are required forpathogenesis and result in partial loss of transactivation function(i.e., an androgen insensitivity) and a poorly understood neuromusculardegeneration. Support of use antiandrogen comes in a report in which theantiandrogen flutamide protects male mice from androgen-dependenttoxicity in three models of spinal bulbar muscular atrophy (Renier K J,Troxell-Smith S M, Johansen J A, Katsuno M, Adachi H, Sobue G, Chua J P,Sun Kim H, Lieberman A P, Breedlove S M, Jordan C L. Endocrinology 2014,155(7), 2624-2634). Currently there are no disease-modifying treatmentsbut rather only symptom directed treatments. Efforts to target the polyQAR of Kennedy's disease as the proximal mediator of toxicity byharnessing cellular machinery to promote its degradation, i.e., throughthe use of a SARD, hold promise for therapeutic intervention. Selectiveandrogen receptor degraders such as those reported herein bind to anddegrade all androgen receptors tested (full length, splice variant,antiandrogen resistance mutants, etc.) so degradation of polyQ ARpolymorphism is also expected, indicating that they are promising leadsfor treatment of SBMA.

Here we describe, inter alia, pyrrole, pyrazole, triazole, imidazole,and morpholine based selective androgen receptor degrader (SARD)compounds that may bind to the LBD and/or an alternate binding anddegradation domain (BDD) located in the NTD, antagonize AR, and degradeAR thereby blocking ligand-dependent and ligand-independent ARactivities. This novel mechanism produces improved efficacy when dosedsystemically (e.g., for prostate cancer) or topically (e.g.,dermatological diseases).

SUMMARY OF THE INVENTION

In one aspect, this invention provides a method of treating prostatecancer in a subject in need thereof, wherein said subject has ARoverexpressing prostate cancer, castration-resistant prostate cancer,castration-sensitive prostate cancer, AR-V7 expressing prostate cancer,or d567ES expressing prostate cancer, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound represented by the structure offormula I

wherein

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   X is CH or N;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;    -   A is R² or R³;    -   R² is a five or six-membered saturated or unsaturated ring        having at least one nitrogen atom and 0, 1, or 2 double bonds,        optionally substituted with at least one of Q¹, Q², Q³ and Q⁴,        each independently selected from hydrogen, keto, substituted or        unsubstituted linear or branched alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted        aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN,        NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR,        N(R)₂, NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof;

wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

In one embodiment, the SARD compound is represented by the structure offormula IA:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula I, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one aspect, the SARD compound is represented by the structure offormula IB:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula I, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula II:

wherein

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   X is CH or N;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;    -   A is R² or R³    -   R² is a pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole,        imidazole, imidazolidine, or morpholine ring, said ring        optionally substituted with at least one of Q¹, Q², Q³ and Q⁴,        each independently selected from hydrogen, keto, substituted or        unsubstituted linear or branched alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted        aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN,        NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR,        N(R)₂, NHCOR, CONHR, COOR or COR;    -   R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴,        OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴),        CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂,        NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate,        isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate,        triflate, PO(OH)₂ or OPO(OH)₂; and    -   R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl,        wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl        groups are optionally substituted;    -   or its optical isomer, isomer, pharmaceutically acceptable salt,        pharmaceutical product, hydrate or any combination thereof;    -   wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or        the aniline ring forms a fused heterocyclic ring.

In one embodiment, the SARD compound is represented by the structure offormula IIA:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula II, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula IIB:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula II, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VII:

wherein

-   -   X is CH or N;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z        form a 5 to 8 membered fused ring;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and    -   Q², Q³ and Q⁴ are each independently selected from hydrogen,        keto, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or        unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl,        Br, I, CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide,        NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; or its optical isomer,        isomer, pharmaceutically acceptable salt, pharmaceutical        product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VIIA:

wherein T, R¹, Y, Z, X, Q², Q³, and Q⁴ are as described in the compoundof formula VII, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VIIB:

wherein T, R¹, Y, Z, X, Q², Q³, and Q⁴ are as described in the compoundof formula VII, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, in the compounds of formulas I, IA, IB, IIA, and/orIIB, Q¹, Q², Q³ and/or Q⁴ is hydrogen, CN, NO₂, CF₃, F, Cl, Br, I,NHCOOR, N(R)₂, NHCOR, COR, or substituted or unsubstituted phenyl.

In one embodiment, the SARD compound is represented by the structure ofany one of the following compounds:

In one embodiment, the castration-resistant prostate cancer in themethod of the invention is AR overexpressing castration-resistantprostate cancer, F876L mutation expressing castration-resistant prostatecancer, F876L_T877A double mutation expressing castration-resistantprostate cancer, AR-V7 expressing castration-resistant prostate cancer,d567ES expressing castration-resistant prostate cancer, and/orcastration-resistant prostate cancer characterized by intratumoralandrogen synthesis.

In one embodiment, the castration-sensitive prostate cancer in themethod of the invention is F876L mutation expressingcastration-sensitive prostate cancer, F876L_T877A double mutationcastration-sensitive prostate cancer, and/or castration-sensitiveprostate cancer characterized by intratumoral androgen synthesis.

In one embodiment, the treating of castration-sensitive prostate cancerin the method of the invention is conducted in a non-castrate setting,or as monotherapy, or when castration-sensitive prostate cancer tumor isresistance to enzalutamide, apalutamide, and/or abiraterone.

In one aspect, this invention provides a method of treating breastcancer in a subject in need thereof, wherein said subject has ARexpressing breast cancer, AR-SV expressing breast cancer, and/or AR-V7expressing breast cancer, comprising administering to the subject atherapeutically effective amount of a selective androgen receptordegrader (SARD) compound represented by the structure of formula I:

wherein

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   X is CH or N;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;    -   A is R² or R³;    -   R² is a five or six-membered saturated or unsaturated ring        having at least one nitrogen atom and 0, 1, or 2 double bonds,        optionally substituted with at least one of Q¹, Q², Q³ and Q⁴,        each independently selected from hydrogen, keto, substituted or        unsubstituted linear or branched alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted        aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN,        NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR,        N(R)₂, NHCOR, CONHR, COOR or COR;    -   R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴,        OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴),        CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂,        NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate,        isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate,        triflate, PO(OH)₂ or OPO(OH)₂; and    -   R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl,        wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl        groups are optionally substituted;    -   or its optical isomer, isomer, pharmaceutically acceptable salt,        pharmaceutical product, hydrate or any combination thereof;    -   wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or        the aniline ring forms a fused heterocyclic ring.

In one embodiment, the SARD compound is represented by the structure offormula IA:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula I, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula IB:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula I, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula II:

wherein

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   X is CH or N;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;    -   A is R² or R³    -   R² is a pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole,        imidazole, imidazolidine, or morpholine ring, said ring        optionally substituted with at least one of Q¹, Q², Q³ and Q⁴,        each independently selected from hydrogen, keto, substituted or        unsubstituted linear or branched alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted        aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN,        NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR,        N(R)₂, NHCOR, CONHR, COOR or COR;    -   R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴,        OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴),        CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂,        NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate,        isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate,        triflate, PO(OH)₂ or OPO(OH)₂; and    -   R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl,        wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl        groups are optionally substituted;    -   or its optical isomer, isomer, pharmaceutically acceptable salt,        pharmaceutical product, hydrate or any combination thereof;    -   wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or        the aniline ring forms a fused heterocyclic ring.

In one embodiment, the SARD compound is represented by the structure offormula IIA:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula II, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula IIB:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula II, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VII:

wherein

-   -   X is CH or N;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and    -   Q², Q³ and Q⁴ are each independently selected from hydrogen,        keto, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or        unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl,        Br, I, CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide,        NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; or its optical isomer,        isomer, pharmaceutically acceptable salt, pharmaceutical        product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VIIA:

wherein T, R¹, Y, Z, X, Q², Q³, and Q⁴ are as described in the compoundof formula VII, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VIIB:

wherein T, R¹, Y, Z, X, Q², Q³, and Q⁴ are as described in the compoundof formula VII, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, in the compounds of formulas I, IA, IB, II, IIA, andIIB, Q¹, Q², Q³ and/or Q⁴ is hydrogen, CN, NO₂, CF₃, F, Cl, Br, I,NHCOOR, N(R)₂, NHCOR, COR, or substituted or unsubstituted phenyl.

In one embodiment, the SARD compound is represented by the structure ofany one of the following compounds:

In one aspect, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hormonal condition in a male in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a selective androgen receptor degrader (SARD)compound represented by the structure of formula I:

wherein

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   X is CH or N;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl,    -   F, Cl, Br, I, or OH;    -   A is R² or R³;    -   R² is a five or six-membered saturated or unsaturated ring        having at least one nitrogen atom and 0, 1, or 2 double bonds,        optionally substituted with at least one of Q¹, Q², Q³ and Q⁴,        each independently selected from hydrogen, keto, substituted or        unsubstituted linear or branched alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted        aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN,        NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR,        N(R)₂, NHCOR, CONHR, COOR or COR;    -   R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴,        OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴),        CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂,        NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate,        isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate,        triflate, PO(OH)₂ or OPO(OH)₂; and    -   R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl,        wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl        groups are optionally substituted;    -   or its optical isomer, isomer, pharmaceutically acceptable salt,        pharmaceutical product, hydrate or any combination thereof;    -   wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or        the aniline ring forms a fused heterocyclic ring.

In one embodiment, the SARD compound is represented by the structure offormula IA:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula I, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula IB:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula I, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula II:

wherein

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   X is CH or N;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl,    -   F, Cl, Br, I, or OH;    -   A is R² or R³    -   R² is a pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole,        imidazole, imidazolidine, or morpholine ring, said ring        optionally substituted with at least one of Q¹, Q², Q³ and Q⁴,        each independently selected from hydrogen, keto, substituted or        unsubstituted linear or branched alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted        aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN,        NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR,        N(R)₂, NHCOR, CONHR, COOR or COR;    -   R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴,        OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴),        CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂,        NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate,        isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate,        triflate, PO(OH)₂ or OPO(OH)₂; and    -   R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl,        wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl        groups are optionally substituted;    -   or its optical isomer, isomer, pharmaceutically acceptable salt,        pharmaceutical product, hydrate or any combination thereof;    -   wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or        the aniline ring forms a fused heterocyclic ring.

In one embodiment, the SARD compound is represented by the structure offormula IIA:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula II, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula IIB:

wherein T, R¹, Y, Z, X, and A are as described in the compound offormula II, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VII:

wherein

-   -   X is CH or N;    -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;    -   Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,    -   or Y and Z form a 5 to 8 membered fused ring;    -   R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;    -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and    -   Q², Q³ and Q⁴ are each independently selected from hydrogen,        keto, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or        unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl,        Br, I, CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide,        NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; or its optical isomer,        isomer, pharmaceutically acceptable salt, pharmaceutical        product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VIIA:

wherein T, R¹, Y, Z, X, Q², Q³, and Q⁴ are as described in the compoundof formula VII, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, the SARD compound is represented by the structure offormula VIIB:

wherein T, R¹, Y, Z, X, Q², Q³, and Q⁴ are as described in the compoundof formula VII, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate or any combination thereof.

In one embodiment, in the compound of formulas I, IA, IB, II, IIA, andIIB, Q¹, Q², Q³ and Q⁴ are hydrogen, CN, NO₂, CF₃, F, Cl, Br, I, NHCOOR,N(R)₂, NHCOR, COR, or substituted or unsubstituted phenyl.

In one embodiment, the SARD compound is represented by the structure ofany one of the following compounds:

In one embodiment, the condition in the method of the invention ishypergonadism, hypersexuality, sexual dysfunction, gynecomastia,precocious puberty in a male, alterations in cognition and mood,depression, hair loss, hyperandrogenic dermatological disorders,pre-cancerous lesions of the prostate, benign prostate hyperplasia,prostate cancer and/or other androgen-dependent cancers.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings.

FIGS. 1A-1C: The transactivation result of 1002 was reported based onmeasured luciferase light emissions and reported as relative light unitintensity (RLU). FIG. 1A plotted the results with RLU reported on they-axis and SARD concentration on the x-axis, where the antagonist modewas reported in closed dots. A curve was fitted to the closed dots. FIG.1B illustrates the Western blot of the androgen receptor degradationassay with AD1 cells and the results were reported in Table 1, underSARD Activity: Full Length % Inhibition. FIG. 1C illustrates the Westernblot of the androgen receptor degradation splice variant assay withD567es cells. (The results in 22RV1 cells were reported in Table 1,under ‘SARD Activity: S.V. % Inhibition’.)

FIG. 2A and FIG. 2B: The transactivation results for 11 (an indole) and1002 (a pyrazole of this invention) were reported based on measuredluciferase light emissions and reported as relative light unit intensity(RLU). FIG. 2A plotted the results with RLU reported on the y-axis andSARD concentration on the x-axis, where the antagonist mode was reportedfor 11 and 1002. Compound 11 is represented in closed dots and solidline and 1002 is represented in open dots and dashed line. A curve wasfitted to the open and closed dots for 1002 and 11, respectively. FIG.2B illustrates the Western blots of an AR degradation assay with AD1cells (Full Length AR) and a splice variant assay with 22RV1 cells for11, 11R (R-isomer of 11), 1002, and 1020 (R-isomer of 1002). The resultswere reported in Table 1 in columns labeled ‘SARD Activity: Full Length% Inhibition’ and ‘SARD Activity: S.V. % Inhibition’, respectively. Inshort, the R-isomer of indole and pyrazole SARDs retained SARD activity,in contrast to LBD-dependent inhibitors.

FIG. 3A and FIG. 3B: The transactivation result of 1003 was reportedbased on measured luciferase light emissions and reported as relativelight unit intensity (RLU). FIG. 3A plotted the results with RLUreported on the y-axis and SARD concentration on the x-axis, where theagonist mode was reported in closed dots and the antagonist mode wasreported in open dots. A curve was fitted to the open dots. FIG. 3Billustrates the Western blot of the full length androgen receptordegradation assay and the results were reported in Table 1, under SARDActivity: Full Length % Inhibition.

FIG. 4A and FIG. 4B: The transactivation result of 1004 was reportedbased on measured luciferase light emissions and reported as relativelight unit intensity (RLU). FIG. 4A plotted the results with RLUreported on the y-axis and SARD concentration on the x-axis, where theagonist mode was reported in closed dots and antagonist mode wasreported in open dots. A curve was fitted to the open dots. FIG. 4Billustrates the Western blot of the full length androgen receptordegradation assay and the results were reported in Table 1, under SARDActivity: Full Length % Inhibition. The numbers under the Western blotindicate the ratio of AR to actin in each lane.

FIG. 5A and FIG. 5B: The transactivation results of 1005 were reportedbased on measured luciferase light emissions and reported as relativelight unit intensity (RLU). FIG. 5A plotted the results with RLUreported on the y-axis and SARD concentration on the x-axis, where theagonist mode was reported in closed dots and antagonist mode wasreported in open. A curve was fitted to the open dots. FIG. 5Billustrates the Western blot of the full length androgen receptordegradation assay and the results were reported in Table 1, under SARDActivity: Full Length % Inhibition.

FIG. 6A and FIG. 6B: The transactivation result of 1006 was reportedbased on measured luciferase light emissions and reported as relativelight unit intensity (RLU). FIG. 6A plotted the results with RLUreported on the y-axis and SARD concentration on the x-axis, where theagonist mode was reported in closed dots and antagonist mode wasreported in open dots. A curve was fitted to the open dots. FIG. 6Billustrates the Western blot of the full length androgen receptordegradation assay and the results were reported in Table 1, under SARDActivity: Full Length % Inhibition.

FIG. 7: The Western blot of the full length androgen receptordegradation assay is shown for compound 17 and the results are reportedin Table 1, under SARD Activity: Full Length % Inhibition.

FIG. 8: The transactivation result of 1011 was reported based onmeasured luciferase light emissions and reported as relative light unitintensity (RLU). FIG. 8 plotted the results with RLU reported on they-axis and SARD concentration on the x-axis, where the antagonist modewas reported in closed dots. A curve was fitted to the closed dots.

FIG. 9: The transactivation result of 1010 was reported based onmeasured luciferase light emissions and reported as relative light unitintensity (RLU). FIG. 9 plotted the results with RLU reported on they-axis and SARD concentration on the x-axis, where the antagonist modewas reported in closed dots. A curve was fitted to the closed dots.

FIG. 10: The transactivation result of 1009 was reported based onmeasured luciferase light emissions and reported as relative light unitintensity (RLU). FIG. 10 plotted the results with RLU reported on they-axis and SARD concentration on the x-axis, where the antagonist modewas reported in closed dots. A curve was fitted to the closed dots.

FIG. 11: The transactivation result of 1008 was reported based onmeasured luciferase light emissions and reported as relative light unitintensity (RLU). FIG. 11 plotted the results with RLU reported on they-axis and SARD concentration on the x-axis, where the antagonist modewas reported in closed dots. A curve was fitted to the closed dots.

FIG. 12: The transactivation result of 1007 was reported based onmeasured luciferase light emissions and reported as relative light unitintensity (RLU). FIG. 12 plotted the results with RLU reported on they-axis and SARD concentration on the x-axis, where the antagonist modewas reported in closed dots. A curve was fitted to the closed dots.

FIGS. 13A-13C: The transactivation result of 1001 was reported based onmeasured luciferase light emissions and reported as relative light unitintensity (RLU). FIG. 13A plotted the results with RLU reported on they-axis and SARD concentration on the x-axis, where the antagonist modewas reported in closed dots. A curve was fitted to the closed dots. FIG.13B illustrates the Western blot of the full length androgen receptordegradation assay and the results were reported in Table 1, under SARDActivity: Full Length % Inhibition. FIG. 13C illustrates the Westernblot of the androgen receptor degradation splice variant assay with22RV1 cells and the results were reported in Table 1, under SARDActivity: S.V. % Inhibition.

FIG. 14: FIG. 14 illustrates the phase I and phase I & II data as a rawdata table for the determination of metabolic stability for 1002 inmouse liver microsomes (MLM) and the T_(1/2) (half-life in minutes) andCL_(int) (clearance in μL/min/mg protein) values calculated therefrom.

FIG. 15A and FIG. 15B: FIG. 15A reports phase I data as a raw data tableand graphed data for one experiment for 1002 in mouse liver microsomes(MLM). FIG. 15B reports phase I & II data as a raw data table andgraphed data for one experiment for 1002 in mouse liver microsomes(MLM). Value for T_(1/2) was 224 min. CL_(int) was 3.12 μL/min/mg.

FIG. 16A and FIG. 16B: FIG. 16A reports phase I data for human livermicrosomes (HLM). FIG. 16B reports phase I & II data as a raw data tableand graphed data for one experiment for 1002 in human liver microsomes(HLM). For this experiment, the calculated value for T_(1/2) wasinfinity and CL_(int) was 0. Suggesting greater stability for 1002 inHLM than MLM.

FIG. 17: FIG. 17 reports phase I data as a raw data table and grapheddata for one experiment for 1001 in mouse liver microsomes (MLM). Valuefor T_(1/2) was 23.5 min and CL_(int) was 29.5 μL/min/mg. Results depictrelatively poor stability for 1001, but still an improvement compared to11.

FIG. 18A and FIG. 18B: Hershberger method (mice): Male mice (20-25 gramsbody weight; n=5-7/group) were either left intact (FIG. 18A) orcastrated (FIG. 18B) and treated as indicated in the figures for 13days. Treatment of castrated mice was initiated 3 days after castration.Mice were sacrificed on day 14 after treatment initiation and seminalvesicles were removed and weighed. Seminal vesicles weights were eitherrepresented as is or were normalized to body weight and represented.

FIG. 19A and FIG. 19B: Hershberger method (rat): FIG. 19A reportsweights organs in intact Sprague Dawley rats with body weights of165-180 grams treated daily with vehicle, 40 mg/kg 1002, 60 mg/kg 1002,or 20 mg/kg enzalutamide orally. After 13 days of treatment, the ratswere sacrificed and the weights of prostate, seminal vesicles, andlevator ani were measured. FIG. 19B reports the same data as a %decrease from vehicle. Bottom right pane illustrates intact vs.castrated % organ weights for vehicle treated rats.

FIG. 20A and FIG. 20B: Degradation of full length and splice variant(AR-v567ES) androgen receptors (in vitro) for 1010, 1012, 1014, 1015,1016, 1017, 1019 and 1022: FIG. 20A illustrates for each compound theWestern blot of the full length androgen receptor degradation assay. Theresults were reported in Table 1, under SARD Activity: Full Length %Inhibition. FIG. 20B illustrates the Western blot of the androgenreceptor degradation splice variant assay with D567es.

FIG. 21A and FIG. 21B: Anti-tumor efficacy for 1002 in triple negativebreast cancer (TNBC) patient-derived xenograft (PDX) is presented inHBrt 1071 triple negative breast cancer (FIG. 21A) and in HBrt 1361triple negative breast cancer (FIG. 21B).

FIG. 22: depicts binding of 1002 to AF-1 region of the N-terminal domain(NTD) of the androgen receptor. 1D and waterLogsy NMR experimentsdemonstrate that 1002 bandwidth are broadened in the presence of apeptide derived from the AF-1 region of the NTD. Moreover, relaxationand waterLogsy demonstrate that the tumbling rate in solution for 1002is slowed upon addition of AF-1, strongly suggestive of 1002 binding toAF-1 region as its targeted protein interaction.

FIG. 23: depicts a LNCaP-enzalutamide resistant (LNCaP-EnzR) cells MR49Fgrowth assay using 1002 and 1014. 1002 and 1014 inhibit the growth ofLNCaP-EnzR cells in the low micromolar range.

FIG. 24: depicts the serum and tumor levels of 11, 34, 36, 96, 103,1002, 1010, 1012, and 1014 achieved in a 22RV1 xenograft experiment.

FIG. 25: depicts reductions in seminal vesicles weights (% change) foranimals treated with 34, 36, 1002, 1010, 1012, and 1014 in a Hershbergerassay.

FIG. 26: depicts tumor growth inhibition of LNCaP-enzalutamide-resistant(LNCaP-EnzR) xenografts treated with 1014 at 60 mg/kg administeredorally. Two different experiments (Experiment 1 and Experiment 2) areshown.

FIGS. 27A-27D: depict steady state fluorescence studies demonstratinginteractions between SARDs 1002, 1010, and 36 (indole), and N-terminalfragments of the AR such AR-NTD (amino acids 1-559) and AR-AF1 (aminoacids 141-486). FIG. 27A depicts the perturbation of the fluorescentsignal of AR-NTD and AR-AF1 in the presence of urea (denaturant), TMAO(folding stabilizer), and buffer, but no SARD. FIGS. 27B-27D depict theperturbations of AR-NTD and AR-AF1 fluorescence associated with thetitrations of 1002 (FIG. 27B), 1010 (FIG. 27C), and 36 (FIG. 27D),respectively.

FIGS. 28A-28D: depicts degradation of full length and/or splice variant(22RV1) androgen receptors (in vitro) for 1024 (FIG. 28A), 1029 (FIG.28B), 1037 and 1041 (FIG. 28C), and 1044-1045 (FIG. 28D). FIGS. 28A,28C, and 28D illustrate the Western blots of the full length androgenreceptor degradation assay. The results were reported in Table 1, underSARD Activity: Full Length % Inhibition. FIG. 28B illustrates theWestern blots of the androgen receptor degradation splice variant assaywith 22RV1 cells which are represented in Table 1 in the column labeled‘SARD Activity: S.V. % Inhibition’.

FIGS. 29A-29C: depict that SARDs such as 1002 can antagonize F876L AR atdoses comparable to the wildtype AR and W741L AR at more potent dosesthan wildtype AR. (FIG. 29A) Enzalutamide inhibited F876L AR at dosesmore potent than wildtype AR but was a weaker antagonist of W741L AR(FIG. 29B). However, when the assay was run in agonist mode (FIG. 29C),enzalutamide, at higher doses acted as an agonist of F876L AR. This ischaracteristic of agonist switch mutations in which AR antagonists ofwildtype AR become AR agonists in due to the AR mutation. By comparison,SARDs like 1002 possess no intrinsic transcriptional agonist activity onwildtype AR or F876L AR, suggesting that tumors possessing agonistswitch mutations can be inhibited by SARDs of this invention. Similarly,W741L is an agonist switch mutation conferring resistance tobicalutamide, which is inhibited by SARDs. FIG. 30E demonstrates thatSARDs of this invention can degrade F876L AR.

FIGS. 30A-30E: SARDs degrade the AR, AR-SV, and AR-F876L (MR49F), butnot PR and ER (see ZR-75-1 cells). FIG. 30A: LNCaP (compound 11); FIG.30B: LNCaP (compound 1002); FIG. 30C: ZR-75-1 (compound 1002); FIG. 30D:LNCaP-AR-V7 (compounds 11 and 1002); and FIG. 30E: MR49F (compound1002). LNCaP cells possess the T877A mutation which confers resistanceto flutamide (or hydroxyflutamide, the active metabolite) whichdemonstrates that SARDs will degrade an agonist switch mutant AR.Likewise, the F876L AR mutation confers resistance to enzalutamide andabiraterone and FIG. 30E demonstrates the ability to degrade thismutant. Cumulatively, this is good evidence that agonist switchmutations to current anti-androgens can be overcome with the SARDs ofthis invention.

FIGS. 31A and 31B: SARDs promote ubiquitination and require theproteasome to degrade the AR. FIG. 31A: compounds 11 and 1002; and FIG.31B: compound 1002 and bortezomib. The FIG. 31A shows an immunoblot inwhich a fusion portion with AR connected to hemagglutinin (HA) isexpressed in cells. Then the cells are treated with the indicated SARDsor untreated, the AR complex is immunoprecipitated with anti-HA, and runon a Western blot and visualized with anti-ubiquitin antibody (anti-Ub).In the untreated lane, there is no observed ubiquitination of AR,whereas there is various degrees of ubiquitination of AR in the SARD (11and 1002) treated lanes which are apparent as a smear of AR molecularweights extending up from the fusion protein molecular weight. Thisindicated that the SARDs induced the ubiquitination of AR. Relative ARlevels are shown under each lane (10% input: AR). FIG. 31B indicatesthat 1002 degrades AR at 10 micromolar in the presence of 50 micromolarcycloheximide. Further, bortezomib, a protease inhibitor, does notinduce AR expression at 1, 5 and 10 micromolar. However, co-treatment ofcells with 1002 and 1, 5 and 10 micromolar resulted in a dose responsivereversal of the SARD activity of 1002. Reversal of SARD activity by aproteasome inhibitor indicates that the 1002 and other SARDs of thisinvention work by a proteasome-dependent protein degradation pathway.

FIG. 32: SARDs require AR-NTD containing constructs (e.g. AR or AGGchimera) to degrade the AR whereas SARDs were unable to degrade GR-NTDcontaining constructs (GR and GAA chimera).

FIG. 33: SARDs inhibit the growth of enzalutamide-resistant VCaP CPRCxenografts in rats. The graph of tumor volume (TV) over time of VCaPCRPC in rats showed the ability of compound 1002 in rats (there is lessmetabolism of compound 1002 in rats than mice) to completely resolveVCaP xenografts (tumor volumes plotted as triangles) within 21 days,whereas enzalutamide only caused partial regression (tumor volumesplotted as squares). VCaP is an androgen-dependent CRPC cell line thatis partially sensitive to enzalutamide, but fully sensitive to SARDs ofthis invention. Cai et al. (PM ID: 21868758) have characterized VCaPcells as expressing high levels of androgen biosynthesis enzymes CYP17A1and AKR1C3 resulting in high intratumoral androgen levels andreactivation of the AR-axis. This model demonstrated that in the absenceof pharmacokinetic barriers (i.e., high levels of metabolism and/or poorabsorption and distribution in mice tumor xenograft models), that SARDscan lead to the complete resolution of castration resistant prostatecancers.

FIGS. 34A-34D: SARDs inhibit AR and Enz-R-AR function and cell growth.FIG. 34A: FKBP5 expression in LNCaP cells; FIG. 34B: Growth inhibitionof LNCaP cells; FIG. 34C: FKBP5 expression in enzalutamide resistant(EnzR)LNCaP cells; and FIG. 34D: Growth inhibition in LNCaP-EnzR cells.1002 inhibited the AR-dependent gene FKBP5 in either LNCaP andLNCaP-EnzR cells demonstrating the ability to inhibit the AR-axis ineither CRPC's such as LNCaP (T877A) or enzalutamide resistant prostatecancers, and, correspondingly, to also inhibit cell growth in theseAR-dependent cell lines whereas enzalutamide was unable to significantlyinhibit FKBP5 or growth in the LNCaP-EnzR cell line.

FIG. 35A: SARDs of this invention regressed the VCaP (enzalutamidesensitive) tumors grown in castrated rats to undetectable levels. FIG.35B shows tumor volume data for the individual animals in thisexperiment. Solid line is vehicle treated rats, larger dashes in theline are for enzalutamide treated rats, and smaller dashes are for 1002treated rats.

FIG. 36A: SARDs inhibited growth of tumor, caused rapid tumorregression, and rapidly reduced PSA serum to zero in a singlecryptorchid animal (i.e., androgen replete milieu) implanted with VCaPcells which were rendered enzalutamide resistant (MDVR). The left paneshows the tumor volume for this animal. The right pane show that 1002immediately and completely reduced PSA to zero, whereas enzalutamidetreated xenograft has only a modest PSA response. FIG. 36B: demonstratesthat vehicle treated and enzalutamide treated MDVR VCaP xenograftcontinued to grow rapidly. This established that the MDVR VCaP model wasa good model of enzalutamide resistance.

FIG. 37 demonstrates that the experiment, when repeated in multiple(N=3) intact (not cryptorchid) rats, again produces rapid and completetumor regression with SARD treatment but rapid growth with enzalutamidetreatment which was similar to vehicle.

FIG. 38 demonstrates that the SARD is able to fully inhibit MDVR VCaPtumors in castrated animals but did not regress the tumors asdramatically as in intact rats, whereas enzalutamide treated tumorsgrowth comparably to vehicle. The preference for intact in this modelwas an unexpected results never before reported anywhere to ourknowledge.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those skilled in the art that thepresent invention may be practiced without these specific details. Inother instances, well-known methods, procedures, and components have notbeen described in detail so as not to obscure the present invention.

Androgens act in cells by binding to the AR, a member of the steroidreceptor superfamily of transcription factors. As the growth andmaintenance of prostate cancer (PCa) is largely controlled bycirculating androgens, treatment of PCa heavily relies on therapies thattarget AR. Treatment with AR antagonists such as enzalutamide,bicalutamide or hydroxyflutamide to disrupt receptor activation has beensuccessfully used in the past to reduce PCa growth. All currentlyavailable AR antagonists competitively bind AR and recruit corepressorssuch as NCoR and SMRT to repress transcription of target genes. However,altered intracellular signaling, AR mutations, and increased expressionof coactivators lead to functional impairment of antagonists or eventransformation of antagonists into agonists. Studies have demonstratedthat mutation of W741 and T877 within AR converts bicalutamide andhydroxyflutamide, respectively, to agonists. Similarly, increasedintracellular cytokines recruit coactivators instead of corepressors toAR-responsive promoters subsequently converting bicalutamide to anagonist. Similarly, mutations that have been linked to enzalutamideresistance include F876, H874, T877, and di-mutants T877/S888,T877/D890, F876/T877 (i.e., MR49 cells), and H874/T877 (Genome Biol.(2016) 17:10 (doi: 10.1186/s13059-015-0864-1)). Abiraterone resistancemutations include L702H mutations which results in activation of the ARby glucocorticoids such as prednisone, causing resistance to abirateronebecause abiraterone is usually prescribed in combination withprednisone. If resistance develops to enzalutamide then often thepatient is refractory to abiraterone also and vice versa; or theduration of response is very short. This situation highlights the needfor a definitive androgen ablation therapy to prevent AR reactivation inadvanced prostate cancers.

Despite initial response to androgen deprivation therapy (ADT), PCadisease progression is inevitable and the cancer emerges ascastration-resistant prostate cancer (CRPC). The primary reason forcastration resistant prostate cancer (CRPC) re-emergence isre-activation of androgen receptor (AR) by alternate mechanisms such as:

-   -   (a) intracrine androgen synthesis;    -   (b) expression of AR splice variants (AR-SV), e.g., that lack        ligand binding domain (LBD);    -   (c) AR-LBD mutations with potential to resist antagonists;    -   (d) hyper-sensitization of AR to low androgen levels, e.g., due        to AR gene amplification or AR mutation;    -   (e) amplification of the AR gene within the tumor; and    -   (f) over expression of coactivators and/or altered intracellular        signal transduction.

The invention encompasses novel selective androgen receptor degrader(SARD) compounds encompassed by formula I, which inhibit the growth ofprostate cancer (PCa) cells and tumors that are dependent on AR fulllength (AR-FL) including pathogenic and resistance mutations andwildtype, and/or AR splice variants (AR-SV) for proliferation.

As used herein, unless otherwise defined, a “selective androgen receptordegrader” (SARD) compound is an androgen receptor antagonist capable ofinhibiting the growth of PCa cells and tumors that are dependent onAR-full length (AR-FL) and/or AR splice variants (AR-SV) forproliferation. The SARD compound may not bind to ligand binding domain(LBD). Alternatively, a “selective androgen receptor degrader” (SARD)compound is an androgen receptor antagonist capable of causingdegradation of a variety of pathogenic mutant variant AR's and wildtypeAR and hence are capable of exerting anti-androgenism is a wide varietyof pathogenic altered cellular environments found in the disease statesembodied in this invention. In one embodiment, the SARD is orallyactive. In another embodiment, the SARD is applied topically to the siteof action.

The SARD compound may bind to the N-terminal domain (NTD) of the AR; toan alternate binding and degradation domain (BDD) of the AR; to both theAR ligand binding domain (LBD) and to an alternate binding anddegradation domain (BDD); or to both the N-terminal domain (NTD) and tothe ligand binding domain (LBD) of the AR. In one embodiment, the BDDmay be located in the NTD. In one embodiment, the BDD is located in theAF-1 region of the NTD. Alternatively, the SARD compound may be capableof: inhibiting growth driven by the N-terminal domain (NTD)-dependentconstitutively active AR-SV; or inhibiting the AR through binding to adomain that is distinct from the AR LBD. Also, the SARD compound may bea strong (i.e., highly potent and highly efficacious) selective androgenreceptor antagonist, which antagonizes the AR stronger than other knownAR antagonists (e.g., enzalutamide, bicalutamide and abiraterone).

The SARD compound may be a selective androgen receptor antagonist, whichtargets AR-SVs, which cannot be inhibited by conventional antagonists.The SARD compound may exhibit any one of several activities including,but not limited to: AR-SV degradation activity; AR-FL degradationactivity; AR-SV inhibitory activity (i.e., is an AR-SV antagonist);AR-FL inhibitory activity (i.e., is an AR-FL antagonist); inhibition ofthe constitutive activation of AR-SVs; or inhibition of the constitutiveactivation of AR-FLs. Alternatively, the SARD compound may possess dualAR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FLdegradation and AR-FL inhibitory functions; or alternatively possess allfour of these activities.

The SARD compound may also degrade AR-FL and AR-SV. The SARD compoundmay degrade the AR through binding to a domain that is distinct from theAR LBD. The SARD compound may possess dual degradation and AR-SVinhibitory functions that are distinct from any available CRPCtherapeutics. The SARD compound may inhibit the re-activation of the ARby alternate mechanisms such as: intracrine androgen synthesis,expression of AR-SV that lack ligand binding domain (LBD) and AR-LBDmutations with potential to resist antagonists, or inhibit re-activatedandrogen receptors present in pathogenic altered cellular environments.

Examples of AR-splice variants include, but are not limited to, AR-V7and ARv567es (a.k.a. AR-V12; S. Sun, et al. Castration resistance inhuman prostate cancer is conferred by a frequently occurring androgenreceptor splice variant. J Clin Invest. (2010) 120(8), 2715-2730).Nonlimiting examples of AR mutations conferring antiandrogen resistanceare: W741L, T877A, and F876L (J. D. Joseph et al. A clinically relevantandrogen receptor mutation confers resistance to second-generationantiandrogens enzalutamide and ARN-509. Cancer Discov. (2013) 3(9),1020-1029) mutations. Many other LBD resistance conferring mutations areknown in the art and will continue to be discovered. AR-V7 is a splicevariant of AR that lacks the LBD (A. H. Bryce & E. S. Antonarakis.Androgen receptor splice variant 7 in castration-resistant prostatecancer: Clinical considerations. Int J Urol. (2016 Jun. 3) 23(8),646-53. doi: 10.1111/iju.13134). It is constitutively active and hasbeen demonstrated to be responsible for aggressive PCa and resistance toendocrine therapy.

The invention encompasses novel selective androgen receptor degrader(SARD) compounds of formulas I-IX, IA-ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB which bind to the AR through an alternate binding anddegradation domain (BDD), e.g., the NTD or AF-1. The SARDs may furtherbind the AR ligand binding domain (LBD).

The SARD compounds may be used in treating CRPC that cannot be treatedwith any other antagonist. The SARD compounds may treat CRPC bydegrading AR-SVs. The SARD compounds may maintain their antagonisticactivity in AR mutants that normally convert AR antagonists to agonists.For instance, the SARD compounds maintain their antagonistic activity toAR mutants W741L, T877A, and F876L (J. D. Joseph et al. A clinicallyrelevant androgen receptor mutation confers resistance tosecond-generation antiandrogens enzalutamide and ARN-509. Cancer Discov.(2013) 3(9), 1020-1029). Alternatively, the SARD compounds elicitantagonistic activity within an altered cellular environment in whichLBD-targeted agents are not effective or in which NTD-dependent ARactivity is constitutively active.

Selective Androgen Receptor Degrader (SARD) Compounds

The invention encompasses selective androgen receptor degrader (SARD)compounds represented by the structure of formula I:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

-   -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,        CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;        -   A is R² or R³;

R² is a five or six-membered saturated or unsaturated ring having atleast one nitrogen atom and 0, 1, or 2 double bonds, optionallysubstituted with at least one of Q¹, Q², Q³, or Q⁴, each independentlyselected from hydrogen, keto, substituted or unsubstituted linear orbranched alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted orunsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I,CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂,NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof;

wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

In various embodiments, the SARD compound of formula I has a chiralcarbon. In other embodiments, the SARD compound of formula I is aracemic mixture. In other embodiments, the SARD compound of formula I isan (S) isomer. In other embodiments, the SARD compound of formula I isan (R) isomer.

The invention encompasses selective androgen receptor degrader (SARD)compounds represented by the structure of formula IA:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

-   -   A is R² or R³;

R² is a five or six-membered saturated or unsaturated ring having atleast one nitrogen atom and 0, 1, or 2 double bonds, optionallysubstituted with at least one of Q¹, Q², Q³, or Q⁴, each independentlyselected from hydrogen, keto, substituted or unsubstituted linear orbranched alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted orunsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I,CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂,NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof;

wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

The invention encompasses selective androgen receptor degrader (SARD)compounds represented by the structure of formula IB:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

A is R² or R³;

R² is a five or six-membered saturated or unsaturated ring having atleast one nitrogen atom and 0, 1, or 2 double bonds, optionallysubstituted with at least one of Q¹, Q², Q³, or Q⁴, each independentlyselected from hydrogen, keto, substituted or unsubstituted linear orbranched alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted orunsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I,CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂,NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof;

wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

The invention encompasses selective androgen receptor degrader (SARD)compounds represented by the structure of formula IC:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

-   -   or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

R² is a five or six-membered saturated or unsaturated ring having atleast one nitrogen atom and 0, 1, or 2 double bonds, optionallysubstituted with at least one of Q¹, Q², Q³, or Q⁴, each independentlyselected from hydrogen, keto, substituted or unsubstituted linear orbranched alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted orunsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I,CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂,NHCOR, CONHR, COOR or COR;

or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.

The invention encompasses selective androgen receptor degrader (SARD)compounds represented by the structure of formula ID:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

-   -   or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ H, is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof;

wherein if R³ is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

The invention encompasses a SARD compound represented by the structureof formula II:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

A is R² or R³;

R² is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline,pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, ormorpholine ring, said ring optionally substituted with at least one ofQ¹, Q², Q³, or Q⁴, each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof;

wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

In various embodiments, the SARD compound of formula II has a chiralcarbon. In other embodiments, the SARD compound of formula II is aracemic mixture. In other embodiments, the SARD compound of formula IIis an (S) isomer. In other embodiments, the SARD compound of formula IIis an (R) isomer.

The invention encompasses a SARD compound represented by the structureof formula IIA:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

-   -   or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

A is R² or R³;

R² is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline,pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, ormorpholine ring, said ring optionally substituted with at least one ofQ¹, Q², Q³, or Q⁴, each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof;wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

The invention encompasses a SARD compound represented by the structureof formula IIB:

wherein

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

A is R² or R³;

R² a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline,pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, ormorpholine ring, said ring optionally substituted with at least one ofQ¹, Q², Q³, or Q⁴, each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof;wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or theaniline ring forms a fused heterocyclic ring.

The invention encompasses a SARD compound represented by the structureof formula III:

wherein

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

A is R² or R³;

R² is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline,pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, ormorpholine ring, said ring optionally substituted with at least one ofQ¹, Q², Q³, or Q⁴, each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR;

R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴,OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴,SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂,CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate,isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and

R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein saidalkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionallysubstituted;

or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof;

wherein if A is Br or I, then the aniline ring forms a fusedheterocyclic ring.

In various embodiments, the SARD compound of formula III has a chiralcarbon. In other embodiments, the SARD compound of formula III is aracemic mixture. In other embodiments, the SARD compound of formula IIIis an (S) isomer. In other embodiments, the SARD compound of formula IIIis an (R) isomer.

The invention encompasses a selective androgen receptor degradercompound represented by the structure of formula IV:

wherein

B¹, B², B³, and B⁴ are each independently carbon or nitrogen;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q¹, Q², Q³, or Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR;wherein if B¹, B², B³, or B⁴ is nitrogen then Q¹, Q², Q³, or Q⁴,respectively, is nothing; or its optical isomer, isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.

In various embodiments, the SARD compound of formula IV has a chiralcarbon. In other embodiments, the SARD compound of formula IV is aracemic mixture. In other embodiments, the SARD compound of formula IVis an (S) isomer. In other embodiments, the SARD compound of formula IVis an (R) isomer.

The invention encompasses a selective androgen receptor degradercompound represented by the structure of formula V:

wherein

B¹ and B² are each independently carbon or nitrogen;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

-   -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q¹, Q², Q³, or Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR;wherein if B¹ or B² is nitrogen then Q¹ or Q², respectively, is nothing;or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.

In various embodiments, the SARD compound of formula V has a chiralcarbon. In other embodiments, the SARD compound of formula V is aracemic mixture. In other embodiments, the SARD compound of formula V isan (S) isomer. In other embodiments, the SARD compound of formula V isan (R) isomer.

The invention encompasses a selective androgen receptor degradercompound represented by the structure of formula VI:

wherein

is a single or double bond;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

-   -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q¹, Q², Q³, or Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; orits optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.

In various embodiments, the SARD compound of formula VI has a chiralcarbon. In other embodiments, the SARD compound of formula VI is aracemic mixture. In other embodiments, the SARD compound of formula VIis an (S) isomer. In other embodiments, the SARD compound of formula VIis an (R) isomer.

The invention encompasses a selective androgen receptor degradercompound represented by the structure of formula VII:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

-   -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q², Q³, or Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; orits optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.

In various embodiments, the SARD compound of formula VII has a chiralcarbon. In other embodiments, the SARD compound of formula VII is aracemic mixture. In other embodiments, the SARD compound of formula VIIis an (S) isomer. In other embodiments, the SARD compound of formula VIIis an (R) isomer.

The invention encompasses a selective androgen receptor degradercompound represented by the structure of formula VIIA:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

-   -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q², Q³, or Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

The invention encompasses a selective androgen receptor degradercompound represented by the structure of formula VIIB:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

-   -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q², Q³, or Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another embodiment, the invention encompasses a selective androgenreceptor degrader compound represented by the structure of formula VIII:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q³ and Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; orits optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.

In another embodiment, the invention encompasses a selective androgenreceptor degrader compound represented by the structure of formulaVIIIA:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q³ and Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another embodiment, the invention encompasses a selective androgenreceptor degrader compound represented by the structure of formulaVIIIB:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

and

Q³ and Q⁴ are each independently selected from hydrogen, keto,substituted or unsubstituted linear or branched alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,haloalkyl, CF₃, substituted or unsubstituted aryl, substituted orunsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR,arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another embodiment, the invention encompasses a selective androgenreceptor degrader compound represented by the structure of formula IX:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q⁴ is selected from hydrogen, keto, substituted or unsubstituted linearor branched alkyl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted orunsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I,CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂,NHCOR, CONHR, COOR or COR; or its optical isomer, isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.

In another embodiment, the invention encompasses a selective androgenreceptor degrader compound represented by the structure of formula IXA:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

-   -   T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;    -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and

Q⁴ is selected from hydrogen, keto, substituted or unsubstituted linearor branched alkyl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted orunsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I,CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂,NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof.

In another embodiment, the invention encompasses a selective androgenreceptor degrader compound represented by the structure of formula IXB:

wherein

X is CH or N;

Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;

Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl,CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;

and

Q⁴ is selected from hydrogen, keto, substituted or unsubstituted linearor branched alkyl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted orunsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I,CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂,NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof.

In one embodiment, A of formula I-III, IA, IB, IIA, and IIB and R² offormula IC is a five or six-membered saturated or unsaturated ringhaving at least one nitrogen atom. In another embodiment, A is asubstituted or unsubstituted pyrrole, pyrroline, pyrrolidine, pyrazole,pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine,triazole, tetrazole, pyridine, morpholine, or other heterocyclic ring.Each represents a separate embodiment of this invention. In anotherembodiment, A is a five or six-membered heterocyclic ring. In anotherembodiment, a nitrogen atom of the five or six membered saturated orunsaturated ring is attached to the backbone structure of the molecule.In another embodiment, a carbon atom of the five or six memberedsaturated or unsaturated ring is attached to the backbone structure ofthe molecule.

In one embodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ offormula ID is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴,OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴),CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂,NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate, isocyanate,thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ orOPO(OH)₂; wherein R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl orheteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl orheteroaryl groups are optionally substituted.

In one embodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ offormula ID is NHR². In one embodiment, A of formula I-III, IA, IB, IIA,and IIB and R³ of formula ID is halide. In one embodiment, A of formulaI-III, IA, IB, IIA, and IIB and R³ of formula ID is F. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is Br. In one embodiment, A of formula I-III, IA, IB, IIA, and IIBand R³ of formula ID is Cl. In one embodiment, A of formula I-III, IA,IB, IIA, and IIB and R³ of formula ID is I. In one embodiment, A offormula I-III, IA, IB, IIA, and IIB and R³ of formula ID is N₃. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is OR⁴. In one embodiment, A of formula I-III, IA, IB, IIA, and IIBand R³ of formula ID is CF₃. In one embodiment, A of formula I-III, IA,IB, IIA, and IIB and R³ of formula ID is COR⁴. In one embodiment, A offormula I-III, IA, IB, IIA, and IIB and R³ of formula ID is COCl. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is COOCOR⁴. In one embodiment, A of formula I-III, IA, IB, IIA, andIIB and R³ of formula ID is COOR⁴. In one embodiment, A of formulaI-III, IA, IB, IIA, and IIB and R³ of formula ID is OCOR⁴. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is OCONHR⁴. In one embodiment, A of formula I-III, IA, IB, IIA, andIIB and R³ of formula ID is NHCOOR⁴. In one embodiment, A of formulaI-III, IA, IB, IIA, and IIB and R³ of formula ID is NHCONHR⁴. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is OCOOR⁴. In one embodiment, A of formula I-III, IA, IB, IIA, andIIB and R³ of formula ID is CN. In one embodiment, A of formula I-III,IA, IB, IIA, and IIB and R³ of formula ID is CON(R⁴)₂. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is SR⁴. In one embodiment, A of formula I-III, IA, IB, IIA, and IIBand R³ of formula ID is SO₂R⁴. In one embodiment, A of formula I-III,IA, IB, IIA, and IIB and R³ of formula ID is SOR⁴. In one embodiment, Aof formula I-III, IA, IB, IIA, and IIB and R³ of formula ID is SO₃H. Inone embodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ offormula ID is SO₂NH₂. In one embodiment, A of formula I-III, IA, IB,IIA, and IIB and R³ of formula ID is SO₂NH(R⁴). In one embodiment, A offormula I-III, IA, IB, IIA, and IIB and R³ of formula ID is SO₂N(R⁴)₂.In one embodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ offormula ID is NH₂. In one embodiment, A of formula I-III, IA, IB, IIA,and IIB and R³ of formula ID is NH(R⁴). In one embodiment, A of formulaI-III, IA, IB, IIA, and IIB and R³ of formula ID is N(R⁴)₂. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is CONH₂. In one embodiment, A of formula I-III, IA, IB, IIA, and IIBand R³ of formula ID is CONH(R⁴). In one embodiment, A of formula I-III,IA, IB, IIA, and IIB and R³ of formula ID is CO(N-heterocycle). In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is NO₂. In one embodiment, A of formula I-III, IA, IB, IIA, and IIBand R³ of formula ID is cyanate. In one embodiment, A of formula I-III,IA, IB, IIA, and IIB and R³ of formula ID is isocyanate. In oneembodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ of formulaID is thiocyanate. In one embodiment, A of formula I-III, IA, IB, IIA,and IIB and R³ of formula ID is isothiocyanate. In one embodiment, A offormula I-III, IA, IB, IIA, and IIB and R³ of formula ID is mesylate. Inone embodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ offormula ID is tosylate. In one embodiment, A of formula I-III, IA, IB,IIA, and IIB and R³ of formula ID is triflate. In one embodiment, A offormula I-III, IA, IB, IIA, and IIB and R³ of formula ID is PO(OH)₂. Inone embodiment, A of formula I-III, IA, IB, IIA, and IIB and R³ offormula ID is OPO(OH)₂.

In one embodiment R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl orheteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl orheteroaryl groups are optionally substituted. Each represents a separateembodiment of this invention. In other embodiment, R⁴ is H. In otherembodiments, R⁴ is alkyl. In other embodiments, the alkyl is methyl,ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, neopentyl, iso-pentyl,hexyl, or heptyl, each represents a separate embodiment of thisinvention. In other embodiments, R⁴ is haloalkyl In another embodiment,the haloalkyl is CF₃, CF₂CF₃, iodomethyl, bromomethyl, bromoethyl,bromopropyl, each represents a separate embodiment of the invention. Inother embodiments, R⁴ is cycloalkyl. In other embodiments the cycloalkylis cyclobutyl, cyclopentyl, cyclohexyl. In various embodiments, thealkyl, haloalkyl, cycloalkyl, aryl or heteroaryl of R⁴ are furthersubstituted by one or more groups selected from: halide, CN, CO₂H, OH,SH, NH₂, NO₂, CO₂—(C₁-C₆ alkyl) or O—(C₁-C₆ alkyl); each represents aseparate embodiment of this invention.

In a particular embodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ ishydrogen. In a particular embodiment of formulas I-VI, IA-IC, IIA, orIIB, Q¹ is CN. In a particular embodiment of formulas I-VI, IA-IC, IIA,or IIB, Q¹ is F. In a particular embodiment of formulas I-VI, IA-IC,IIA, or IIB, Q¹ is NCS. In a particular embodiment of formulas I-VI,IA-IC, IIA, or IIB, Q¹ is maleimide. In a particular embodiment offormulas I-VI, IA-IC, IIA, or IIB, Q¹ is NHCOOR. In a particularembodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ is N(R)₂. In aparticular embodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ is CONHR.In a particular embodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ isNHCOR. In a particular embodiment of formulas I-VI, IA-IC, IIA, or IIB,Q¹ is Cl. In a particular embodiment of formulas I-VI, IA-IC, IIA, orIIB, Q¹ is Br. In a particular embodiment of formulas I-VI, IA-IC, IIA,or IIB, Q¹ is I. In a particular embodiment of formulas I-VI, IA-IC,IIA, or IIB, Q¹ is NO₂. In a particular embodiment of formulas I-VI,IA-IC, IIA, or IIB, Q¹ is phenyl. In a particular embodiment of formulasI-VI, IA-IC, IIA, or IIB, Q¹ is 4-fluorophenyl. In a particularembodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ is CF₃. In aparticular embodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ issubstituted or unsubstituted alkyl. In a particular embodiment offormulas I-VI, IA-IC, IIA, or IIB, Q¹ is substituted or unsubstitutedcycloalkyl. In a particular embodiment of formulas I-VI, IA-IC, IIA, orIIB, Q¹ is substituted or unsubstituted heterocycloalkyl. In aparticular embodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ ishaloalkyl. In a particular embodiment of formulas I-VI, IA-IC, IIA, orIIB, Q¹ is substituted or unsubstituted aryl. In a particular embodimentof formulas I-VI, IA-IC, IIA, or IIB, Q¹ is hydroxyl. In a particularembodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ is alkoxy. In aparticular embodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ is OR. Ina particular embodiment of formulas I-VI, IA-IC, IIA, or IIB, Q¹ isarylalkyl. In a particular embodiment of formulas I-VI, IA-IC, IIA, orIIB, Q¹ is amine. In a particular embodiment of formulas I-VI, IA-IC,IIA, or IIB, Q¹ is amide. In a particular embodiment of formulas I-VI,IA-IC, IIA, and IIB, Q¹ is COOR. In a particular embodiment of formulasI-VI, IA-IC, IIA, or IIB, Q¹ is COR. In a particular embodiment offormulas I-VI, IA-IC, IIA, or IIB, Q¹ is keto.

In a particular embodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, orVIIB, Q² is CN. In a particular embodiment of formulas I-VII, IA-IC,IIA, IIB, VIIA, or VIIB, Q² is hydrogen. In a particular embodiment offormulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is keto. In aparticular embodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB,Q² is NCS. In a particular embodiment of formulas I-VII, IA-IC, IIA,IIB, VIIA, or VIIB, Q² is maleimide. In a particular embodiment offormulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is NHCOOR. In aparticular embodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB,Q² is N(R)₂. In a particular embodiment of formulas I-VII, IA-IC, IIA,IIB, VIIA, or VIIB, Q² is CONHR. In a particular embodiment of formulasI-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is NHCOR. In a particularembodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is F.In a particular embodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, orVIIB, Q² is Cl. In a particular embodiment of formulas I-VII, IA-IC,IIA, IIB, VIIA, or VIIB, Q² is Br. In a particular embodiment offormulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is I. In a particularembodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is NO₂.In a particular embodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, orVIIB, Q² is phenyl. In a particular embodiment of formulas I-VII, IA-IC,IIA, IIB, VIIA, or VIIB, Q² is 4-fluorophenyl. In a particularembodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is CF₃.In a particular embodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, orVIIB, Q² is substituted or unsubstituted alkyl. In a particularembodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² issubstituted or unsubstituted cycloalkyl. In a particular embodiment offormulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is substituted orunsubstituted heterocycloalkyl. In a particular embodiment of formulasI-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is haloalkyl. In a particularembodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² issubstituted or unsubstituted aryl. In a particular embodiment offormulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is hydroxyl. In aparticular embodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB,Q² is alkoxy. In a particular embodiment of formulas I-VII, IA-IC, IIA,IIB, VIIA, or VIIB, Q² is OR. In a particular embodiment of formulasI-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is arylalkyl. In a particularembodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² isamine. In a particular embodiment of formulas I-VII, IA-IC, IIA, IIB,VIIA, or VIIB, Q² is amide. In a particular embodiment of formulasI-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is COOR. In a particularembodiment of formulas I-VII, IA-IC, IIA, IIB, VIIA, or VIIB, Q² is COR.

In a particular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA,VIIB, VIIIA or VIIIB, Q³ is CN. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is F. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is NCS. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is maleimide. Ina particular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is NHCOOR. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is N(R)₂. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is CONHR. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³, is NHCOR. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is hydrogen. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is keto. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is Cl. In a particular embodiment of formulas I-VIII,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is Br. In a particularembodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA orVIIIB, Q³ is I. In a particular embodiment of formulas I-VIII, IA-IC,IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is NO₂. In a particularembodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA orVIIIB, Q³ is phenyl. In a particular embodiment of formulas I-VIII,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is 4-fluorophenyl. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is CF₃. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is substitutedor unsubstituted alkyl. In a particular embodiment of formulas I-VIII,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is substituted orunsubstituted cycloalkyl. In a particular embodiment of formulas I-VIII,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is substituted orunsubstituted heterocycloalkyl. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is haloalkyl. Ina particular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is substituted or unsubstituted aryl. In a particularembodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA orVIIIB, Q³ is hydroxyl. In a particular embodiment of formulas I-VIII,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is alkoxy. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is OR. In a particular embodiment of formulas I-VIII,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is arylalkyl. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is amine. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is amide. In aparticular embodiment of formulas I-VIII, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA or VIIIB, Q³ is COOR. In a particular embodiment of formulasI-VIII, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA or VIIIB, Q³ is COR.

In a particular embodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is CN. In a particular embodiment offormulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴is F. In a particular embodiment of formulas I-IX, IA-IC, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is NCS. In a particularembodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA or IXB, Q⁴ is maleimide. In a particular embodiment of formulasI-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ isNHCOOR. In a particular embodiment of formulas I-IX, IA-IC, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is N(R)₂. In a particularembodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA or IXB, Q⁴ is CONHR. In a particular embodiment of formulas I-IX,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴, is NHCOR. Ina particular embodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA or IXB, Q⁴ is hydrogen. In a particular embodiment offormulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴is keto. In a particular embodiment of formulas I-IX, IA-IC, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB B, Q⁴ is Cl. In a particularembodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA or IXB, Q⁴ is Br. In a particular embodiment of formulas I-IX,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is I. In aparticular embodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA or IXB, Q⁴ is NO₂. In a particular embodiment offormulas I-IX, IA-IC, IIA, JIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴is phenyl. In a particular embodiment of formulas I-IX, IA-IC, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is 4-fluorophenyl. In aparticular embodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA or IXB, Q⁴ is CF₃. In a particular embodiment offormulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴is substituted or unsubstituted alkyl. In a particular embodiment offormulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴is substituted or unsubstituted cycloalkyl. In a particular embodimentof formulas I-IX, IA-IC, IIA, JIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB,Q⁴ is substituted or unsubstituted heterocycloalkyl. In a particularembodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA or IXB, Q⁴ is haloalkyl. In a particular embodiment of formulasI-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ issubstituted or unsubstituted aryl. In a particular embodiment offormulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴is hydroxyl. In a particular embodiment of formulas I-IX, IA-IC, IIA,IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is alkoxy. In a particularembodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA or IXB, Q⁴ is OR. In a particular embodiment of formulas I-IX,IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is arylalkyl.In a particular embodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is amine. In a particular embodimentof formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB,Q³ is amide. In a particular embodiment of formulas I-IX, IA-IC, IIA,IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, Q⁴ is COOR. In a particularembodiment of formulas I-IX, IA-IC, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA or IXB, Q⁴ is COR.

In a particular embodiment of formulas I, IA, IB, IC, ID, II, IIA, IIB,VII, VIIA, VIIB, VIII, VIIIA, VIIIB, IX, IXA or IXB, X is CH. In aparticular embodiment of formulas I, IA, IB, IC, ID, II, IIA, IIB, VII,VIIA, VIIB, VIII, VIIIA, VIIIB, IX, IXA or IXB, X is N.

In some embodiments, wherein if A or R³ is Br or I, R¹ is CH₃, and T isOH, then X is N or the aniline ring forms a fused heterocyclic ring.

In a particular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Y is H. In a particularembodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA, or IXB, Y is CF₃. In a particular embodiment offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA,or IXB, Y is F. In a particular embodiment of formulas I-IX, IA, IB, IC,ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Y is I. In aparticular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA, or IXB, Y is Br. In a particular embodiment offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA,or IXB, Y is Cl. In a particular embodiment of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Y is CN. In aparticular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA, or IXB, Y is C(R)₃.

In a particular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Z is H. In a particularembodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA, or IXB, Z is NO₂. In a particular embodiment offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA,or IXB, Z is CN. In a particular embodiment of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Z is a halide.In a particular embodiment of formulas I-VII, IA, IB, IC, ID, IIA, IIB,VIIA, or VIIB, Z is F. In a particular embodiment of formulas I-IX, IA,IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Z is Cl. Ina particular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Z is Br. In a particularembodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA, or IXB, Z is I. In a particular embodiment offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA,or IXB, Z is COOH. In a particular embodiment of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Z is COR. In aparticular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA, or IXB, Z is NHCOR. In a particular embodimentof formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA, or IXB, Z is CONHR.

In a particular embodiment of formulas II-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA, or IXB, Y and Z forms a fused ring withthe phenyl. In other embodiments, the fused ring with the phenyl is a 5to 8 membered ring. In other embodiments, the fused ring with the phenylis a 5 or 6 membered ring. In other embodiments, the ring is acarbocyclic or heterocyclic. In other embodiments, Y and Z form togetherwith the phenyl to form a naphthyl, quinolinyl, benzimidazolyl,indazolyl, indolyl, isoindolyl, indenyl, or quinazolinyl. In aparticular embodiment, Y and Z form together with the phenyl to form aquinazolin-6-yl ring system.

In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII, IXIA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB R¹ is H.In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII, IXIA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, R¹ isCH₃. In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII,IX IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, R¹ isCH₂F. In a particular embodiment of formulas I, II, IV, V, VI, VII,VIII, IX IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB,R¹ is CHF₂. In a particular embodiment of formulas I, II, IV, V, VI,VII, VIII, IX IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA orIXB, R₁ is CF₃. In a particular embodiment of formulas I, II, IV, V, VI,VII, VIII, IX IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA orIXB, R¹ is CH₂CH₃. In a particular embodiment of formulas I, II, IV, V,VI, VII, VIII, IX IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA or IXB, R¹ is CF₂CF₃.

In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII, IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, T is H.In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII, IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, T is OH.In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII, IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, T is OR.In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII, IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, T isOCOR In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII,IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, T isCH₃. In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII,IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, T is—NHCOCH₃. In a particular embodiment of formulas I, II, IV, V, VI, VII,VIII, IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA orIXB, T is NHCOR.

In a particular embodiment of formulas I, II, IV, V, VI, VII, VIII, IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, T and R¹form a 3-8 carbocyclic or heterocyclic ring. In other embodiments, T andR¹ form a 3, 4, 5, 6, 7, or 8 membered carbocyclic or heterocyclic ring.Each represents a separate embodiment of this invention. In someembodiments T and R¹ form a carbocyclic ring such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc. In some embodiments T and R¹form a heterocyclic ring such as piperidine, pyridine, furan, thiophene,pyrrole, pyrazole, pyrimidine, etc.

In a particular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, R is H. In a particular embodimentof formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA, R is alkyl. In a particular embodiment of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, R is alkenyl. In aparticular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA, R is haloalkyl. In a particular embodiment offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA,R is alcohol. In a particular embodiment of formulas I-VII, IA, IB, IC,ID, IIA, IIB, VIIA, or VIIB, R is CH₂CH₂OH. In a particular embodimentof formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB,IXA, R is CF₃. In a particular embodiment of formulas I-VII, IA, IB, IC,ID, IIA, IIB, VIIA, or VIIB, R is CH₂Cl. In a particular embodiment offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA,R is CH₂CH₂Cl. In a particular embodiment of formulas I-IX, IA, IB, IC,ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, R is aryl. In a particularembodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA, R is F. In a particular embodiment of formulas I-IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, R is Cl. In aparticular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA, R is Br. In a particular embodiment of formulasI-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA, R is I.In a particular embodiment of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA, R is OH.

In a particular embodiment of formula IV, Q¹ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula V, Q¹ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VI, Q¹ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula IV, Q² is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula V, Q² is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VI, Q² is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VII, Q² is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VIIA, Q² is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VIIB, Q² is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula IV, Q³ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula V, Q³ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VI, Q³ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VII, Q³ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VIII, Q³ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula IV, Q⁴ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula V, Q⁴ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VI, Q⁴ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VII, Q⁴ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VIIA, Q⁴ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VIIB, Q⁴ is H, CN, CF₃, phenyl,4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe or NHCOOC(CH₃)₃.

In a particular embodiment of formula VIII, VIIIA, or VIIIB, Q⁴ is H,CN, CF₃, phenyl, 4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe orNHCOOC(CH₃)₃.

In a particular embodiment of formula IX, IXA, or IXB, Q⁴ is H, CN, CF₃,phenyl, 4-fluorophenyl, F, Br, Cl, I, COMe, NHCOOMe, NHCOMe orNHCOOC(CH₃)₃.

The invention encompasses a selective androgen receptor degrader (SARD)compound selected from any one of the following structures:

As used herein, the term “heterocycle” or “heterocyclic ring” grouprefers to a ring structure comprising in addition to carbon atoms, atleast one atom of sulfur, oxygen, nitrogen or any combination thereof,as part of the ring. The heterocycle may be a 3-12 membered ring; 4-8membered ring; a 5-7 membered ring; or a 6 membered ring. Preferably,the heterocycle is a 5 to 6 membered ring. Typical examples ofheterocycles include, but are not limited to, piperidine, pyridine,furan, thiophene, pyrrole, pyrrolidine, pyrazole, pyrazine, piperazineor pyrimidine. Examples of C₅-C₈ heterocyclic rings include pyran,dihydropyran, tetrahydropyran, dihydropyrrole, tetrahydropyrrole,pyrazine, dihydropyrazine, tetrahydropyrazine, pyrimidine,dihydropyrimidine, tetrahydropyrimidone, pyrazole, dihydropyrazole,tetrahydropyrazole, triazole, tetrazole, piperidine, piperazine,pyridine, dihydropyridine, tetrahydropyridine, morpholine,thiomorpholine, furan, dihydrofuran, tetrahydrofuran, thiophene,dihydrothiophene, tetrahydrothiophene, thiazole, imidazole, isoxazole,and the like. The heterocycle ring may be fused to another saturated orunsaturated cycloalkyl or a saturated or unsaturated heterocyclic ring.When the heterocycle ring is substituted, the substituents include atleast one of halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido,alkylamido, dialkylamido, cyano, nitro, CO₂H, amino, alkylamino,dialkylamino, carboxyl, thiol, or thioalkyl.

The term “aniline ring system” refers to the conserved ring representedto the left of the structures in this document which is substituted byX, Y, and/or Z.

The term “cycloalkyl” refers to a non-aromatic, monocyclic or polycyclicring comprising carbon and hydrogen atoms. A cycloalkyl group can haveone or more carbon-carbon double bonds in the ring so long as the ringis not rendered aromatic by their presence. Examples of cycloalkylgroups include, but are not limited to, (C₃-C₇) cycloalkyl groups, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl,and saturated cyclic and bicyclic terpenes and (C₃-C₇) cycloalkenylgroups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclicterpenes. Examples of C₅-C₈ carbocyclic include cyclopentane,cyclopentene, cyclohexane, and cyclohexene rings. A cycloalkyl group canbe unsubstituted or substituted by at least one substituent. Preferably,the cycloalkyl group is a monocyclic ring or bicyclic ring.

The term “alkyl” refers to a saturated aliphatic hydrocarbon, includingstraight-chained and branched-chained. Typically, the alkyl group has1-12 carbons, 1-7 carbons, 1-6 carbons, or 1-4 carbon atoms. A branchedalkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons.The branched alkyl may have an alkyl substituted by a C₁-C₅ haloalkyl.Additionally, the alkyl group may be substituted by at least one ofhalogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, CN, amino, alkylamino, dialkylamino, carboxyl, thioor thioalkyl.

An “arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyland aryl are as defined herein. An example of an arylalkyl group is abenzyl group.

An “alkenyl” group refers to an unsaturated hydrocarbon, includingstraight chain and branched chain having one or more double bonds. Thealkenyl group may have 2-12 carbons, preferably the alkenyl group has2-6 carbons or 2-4 carbons. Examples of alkenyl groups include, but arenot limited to, ethenyl, propenyl, butenyl, cyclohexenyl, etc. Thealkenyl group may be substituted by at least one halogen, hydroxy,alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino,alkylamino, dialkylamino, carboxyl, thio, or thioalkyl.

As used herein the term “aryl” group refers to an aromatic group havingat least one carbocyclic aromatic group or heterocyclic aromatic group,which may be unsubstituted or substituted. When present, substituentsinclude, but are not limited to, at least one halogen, haloalkyl,hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino,alkylamino, dialkylamino, carboxy or thio or thioalkyl. Nonlimitingexamples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl,pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl,thiazolyl, imidazolyl, isoxazolyl, and the like. The aryl group may be a4-12 membered ring, preferably the aryl group is a 4-8 membered ring.Also the aryl group may be a 6 or 5 membered ring.

The term “heteroaryl” refers to an aromatic group having at least oneheterocyclic aromatic ring. In one embodiment, the heteroaryl comprisesat least one heteroatom such as sulfur, oxygen, nitrogen, silicon,phosphorous or any combination thereof, as part of the ring. In anotherembodiment, the heteroaryl may be unsubstituted or substituted by one ormore groups selected from halogen, aryl, heteroaryl, cyano, haloalkyl,hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino,alkylamino, dialkylamino, carboxy or thio or thioalkyl. Nonlimitingexamples of heteroaryl rings are pyranyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl,indolyl, imidazolyl, isoxazolyl, and the like. In one embodiment, theheteroaryl group is a 5-12 membered ring. In one embodiment, theheteroaryl group is a five membered ring. In one embodiment, theheteroaryl group is a six membered ring. In another embodiment, theheteroaryl group is a 5-8 membered ring. In another embodiment, theheteroaryl group comprises of 1-4 fused rings. In one embodiment, theheteroaryl group is 1,2,3-triazole. In one embodiment the heteroaryl isa pyridyl. In one embodiment the heteroaryl is a bipyridyl. In oneembodiment the heteroaryl is a terpyridyl.

As used herein, the term “haloalkyl” group refers to an alkyl group thatis substituted by one or more halogen atoms, e.g. by F, Cl, Br or I.

A “hydroxyl” group refers to an OH group. It is understood by a personskilled in the art that when T, Q¹, Q², Q³, or Q⁴, in the compounds ofthe present invention is OR, then R is not OH.

The term “halogen” or “halo” or “halide” refers to a halogen; F, Cl, Bror I.

In one embodiment, this invention provides the compounds and/or its useand/or, its derivative, optical isomer, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or combinations thereof.

In one embodiment, the methods of this invention make use of“pharmaceutically acceptable salts” of the compounds, which may beproduced, by reaction of a compound of this invention with an acid orbase.

The compounds of the invention may be converted into pharmaceuticallyacceptable salts. A pharmaceutically acceptable salt may be produced byreaction of a compound with an acid or base.

Suitable pharmaceutically acceptable salts of amines may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicsalts of amines include, but are not limited to, bisulfates, borates,bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates,2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides,isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates,sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogensubstituted alkylsulfonates, halogen substituted arylsulfonates),sulfonates, or thiocyanates.

Examples of organic salts of amines may be selected from aliphatic,cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which are acetates,arginines, aspartates, ascorbates, adipates, anthranilates, algenates,alkane carboxylates, substituted alkane carboxylates, alginates,benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates,bitartrates, carboxylates, citrates, camphorates, camphorsulfonates,cyclohexylsulfamates, cyclopentanepropionates, calcium edetates,camsylates, carbonates, clavulanates, cinnamates, dicarboxylates,digluconates, dodecylsulfonates, dihydrochlorides, decanoates,enanthuates, ethanesulfonates, edetates, edisylates, estolates,esylates, fumarates, formates, fluorides, galacturonates, gluconates,glutamates, glycolates, glucorates, glucoheptanoates, glycerophosphates,gluceptates, glycollylarsanilates, glutarates, glutamates, heptanoates,hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates,hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates,lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, nitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, pectinates, phenylpropionates, palmitates, pantothenates,polygalacturates, pyruvates, quinates, salicylates, succinates,stearates, sulfanilates, subacetates, tartarates, theophyllineacetates,p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates,tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates,undecanoates and valerates. Examples of inorganic salts of carboxylicacids or phenols may be selected from ammonium, alkali metals, andalkaline earth metals. Alkali metals include, but are not limited to,lithium, sodium, potassium, or cesium. Alkaline earth metals include,but are not limited to, calcium, magnesium, aluminium; zinc, barium,cholines, or quaternary ammoniums. Examples of organic salts ofcarboxylic acids or phenols may be selected from arginine, organicamines to include aliphatic organic amines, alicyclic organic amines,aromatic organic amines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolines, piperazines, procaine,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In various embodiments, the pharmaceutically acceptable salts of thecompounds of this invention include: HCl salt, oxalic acid salt,L-(+)-tartaric acid salt, HBr salt and succinic acid salt. Eachrepresents a separate embodiment of this invention.

Salts may be formed by conventional means, such as by reacting the freebase or free acid form of the product with one or more equivalents ofthe appropriate acid or base in a solvent or medium in which the salt isinsoluble or in a solvent such as water, which is removed in vacuo or byfreeze drying or by exchanging the ions of a existing salt for anotherion or suitable ion-exchange resin.

The methods of the invention may use an uncharged compound or apharmaceutically acceptable salt of the compound. In particular, themethods use pharmaceutically acceptable salts of compounds of formulasI-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB.The pharmaceutically acceptable salt may be an amine salt or a salt of aphenol of the compounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB.

In one embodiment, the methods of this invention make use of a freebase, free acid, non charged or non-complexed compounds of formulasI-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB,and/or its isomer, pharmaceutical product, hydrate, polymorph, orcombinations thereof.

In one embodiment, the methods of this invention make use of an opticalisomer of a compound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA or IXB. In one embodiment, the methods of thisinvention make use of an isomer of a compound of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB. In oneembodiment, the methods of this invention make use of a pharmaceuticalproduct of a compound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA or IXB. In one embodiment, the methods of thisinvention make use of a hydrate of a compound of I-IX, IA, IB, IC, ID,IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB. In one embodiment, themethods of this invention make use of a polymorph of a compound offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXAor IXB. In one embodiment, the methods of this invention make use of ametabolite of a compound of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB. In another embodiment, the methodsof this invention make use of a composition comprising a compound offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXAor IXB, as described herein, or, in another embodiment, a combination ofisomer, metabolite, pharmaceutical product, hydrate, polymorph of acompound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB.

As used herein, the term “isomer” includes, but is not limited to,optical isomers, structural isomers, or conformational isomers.

The term “isomer” is meant to encompass optical isomers of the SARDcompound. It will be appreciated by those skilled in the art that theSARDs of the present invention contain at least one chiral center.Accordingly, the compounds may exist as optically-active (such as an (R)isomer or (S) isomer) or racemic forms. Optically active compounds mayexist as enantiomerically enriched mixtures. Some compounds may alsoexhibit polymorphism. It is to be understood that the present inventionencompasses any racemic, optically active, polymorphic, orstereroisomeric form, or mixtures thereof. Thus, the invention mayencompass SARD compounds as pure (R)-isomers or as pure (S)-isomers. Itis known in the art how to prepare optically active forms. For example,by resolution of the racemic form by recrystallization techniques, bysynthesis from optically active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase.

Compounds of the invention may be hydrates of the compounds. As usedherein, the term “hydrate” includes, but is not limited to, hemihydrate,monohydrate, dihydrate, or trihydrate. The invention also includes useof N-oxides of the amino substituents of the compounds described herein.

This invention provides, in other embodiments, use of metabolites of thecompounds as herein described. In one embodiment, “metabolite” means anysubstance produced from another substance by metabolism or a metabolicprocess.

In one embodiment, the compounds of this invention are preparedaccording to Example 1.

Biological Activity of Selective Androgen Receptor Degraders

A method of treating prostate cancer (PCa) or increasing the survival ofa male subject suffering from prostate cancer comprising administeringto the subject a therapeutically effective amount of a compound or itspharmaceutically acceptable salt, represented by a compound of formulaI:

wherein

T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR;

R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

-   -   or T and R¹ form a 3-8 carbocyclic or heterocyclic ring;        -   Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃;        -   Z H, is NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z            form a 5 to 8 membered ring;    -   X is CH or N;        -   R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃,            CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH;        -   A is R² or R³;    -   R² is a five-membered saturated or unsaturated ring having at        least one nitrogen atom and 0, 1, or 2 double bonds, optionally        substituted with at least one of Q¹, Q², Q³, or Q⁴, each        independently selected from hydrogen, keto, substituted or        unsubstituted linear or branched alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted        aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN,        NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR,        N(R)₂, NHCOR, CONHR, COOR or COR;    -   R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴,        OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH2, CONH(R4),        CON(R4)2, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂,        NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), C(O)(C₁-C₁₀)alkyl, NO₂,        cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate,        tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and    -   R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl,        wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl        groups are optionally substituted;

or its optical isomer, isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.

In another embodiment, if A is Br or I, R¹ is CH₃, and T is OH, then Xis N or the aniline ring forms a fused heterocyclic ring.

A method of treating prostate cancer (PCa) or increasing the survival ofa male subject suffering from prostate cancer comprising administeringto the subject a therapeutically effective amount of a compound or itspharmaceutically acceptable salt, or isomer, represented by a compoundof formulas I-IX, IA-ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB.

The prostate cancer may be advanced prostate cancer, refractory prostatecancer, castration resistant prostate cancer (CRPC), metastatic CRPC(mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or anycombination thereof.

The prostate cancer may depend on AR-FL and/or AR-SV for proliferation.The prostate or other cancer may be resistant to treatment with anandrogen receptor antagonist. The prostate or other cancer may beresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9,flutamide, hydroxyflutamide, nilutamide, cyproterone acetate,ketoconazole, spironolactone, or any combination thereof. The method mayalso reduce the levels of AR, AR-FL, AR-FL with antiandrogenresistance-conferring AR-LBD mutations, AR-SV, gene-amplified AR, or anycombination thereof.

In one embodiment, this invention provides a method of treatingenzalutamide resistant prostate cancer comprising administering to thesubject a therapeutically effective amount of a compound of thisinvention, or its optical isomer, isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof.

In one embodiment, this invention provides a method of treatingabiraterone resistant prostate cancer comprising administering to thesubject a therapeutically effective amount of a compound of thisinvention, or its optical isomer, isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof.

In one embodiment, this invention provides a method of treating triplenegative breast cancer (TNBC) comprising administering to the subject atherapeutically effective amount of a compound of this invention, or itsoptical isomer, isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof.

The method may further comprise a second therapy such as androgendeprivation therapy (ADT) or LHRH agonist or antagonist. LHRH agonistsinclude, but are not limited to, leuprolide acetate.

The invention encompasses a method of treating or inhibiting theprogression of prostate cancer (PCa) or increasing the survival of amale subject suffering from prostate cancer comprising administering tothe subject a therapeutically effective amount of a SARD compound orpharmaceutically acceptable salt, wherein the compound is at least oneof compounds 1001 to 1064.

The invention encompasses a method of treating or inhibiting theprogression of refractory prostate cancer (PCa) or increasing thesurvival of a male subject suffering from refractory prostate cancercomprising administering to the subject a therapeutically effectiveamount of a SARD compound or pharmaceutically acceptable salt, whereinthe compound is represented by a compound of formulas I-IX, IA, IB, IC,ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or the compound isat least one of compounds 1001 to 1064.

The invention encompasses a method of treating or increasing thesurvival of a male subject suffering from castration resistant prostatecancer (CRPC) comprising administering to the subject a therapeuticallyeffective amount of a SARD wherein the compound is represented by acompound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or at least one of compounds 1001 to 1064.

The method may further comprise administering androgen deprivationtherapy to the subject.

The invention encompasses a method of treating or inhibiting theprogression of enzalutamide resistant prostate cancer (PCa) orincreasing the survival of a male subject suffering from enzalutamideresistant prostate cancer comprising administering to the subject atherapeutically effective amount of a SARD compound or pharmaceuticallyacceptable salt, wherein the compound is represented by a compound offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXAor IXB, or the compound is at least one of compounds 1001 to 1064.

The method may further comprise administering androgen deprivationtherapy to the subject.

The invention encompasses a method of treating or inhibiting theprogression of triple negative breast cancer (TNBC) or increasing thesurvival of a female subject suffering from triple negative breastcancer comprising administering to the subject a therapeuticallyeffective amount of a SARD compound or pharmaceutically acceptable salt,wherein the compound is represented by a compound of formulas I-IX, IA,IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or thecompound is at least one of compounds 1001 to 1064.

The invention encompasses a method of treating breast cancer in asubject in need thereof, wherein said subject has AR expressing breastcancer, AR-SV expressing breast cancer, and/or AR-V7 expressing breastcancer, comprising administering to the subject a therapeuticallyeffective amount of a selective androgen receptor degrader (SARD)compound, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,wherein said SARD compound is represented by the structure of formulaI-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, orthe compound is at least one of compounds 1001 to 1064.

The invention encompasses a method of treating AR expressing breastcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof, wherein said SARD compound is represented by thestructure of formula I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or the compound is at least one of compounds 1001 to1064.

The invention encompasses a method of treating AR-SV expressing breastcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof, wherein said SARD compound is represented by thestructure of formula I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or the compound is at least one of compounds 1001 to1064.

The invention encompasses a method of treating AR-V7 expressing breastcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof, wherein said SARD compound is represented by thestructure of formula I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or the compound is at least one of compounds 1001 to1064.

As used herein, the term “increase the survival” refers to a lengtheningof time when describing the survival of a subject. Thus in this context,the compounds of the invention may be used to increase the survival ofmen with advanced prostate cancer, refractory prostate cancer,castration resistant prostate cancer (CRPC); metastatic CRPC (mCRPC);non-metastatic CRPC (nmCRPC); or high-risk nmCRPC; or women with TNBC.

Alternatively, as used herein, the terms “increase”, increasing”, or“increased” may be used interchangeably and refer to an entity becomingprogressively greater (as in size, amount, number, or intensity),wherein for example the entity is sex hormone-binding globulin (SHBG) orprostate-specific antigen (PSA).

The compounds and compositions of the invention may be used forincreasing metastasis-free survival (MFS) in a subject suffering fromnon-metastatic prostate cancer. The non-metastatic prostate cancer maybe non-metastatic advanced prostate cancer, non-metastatic CRPC(nmCRPC), or high-risk nmCRPC.

The SARD compounds described herein may be used to provide a dualaction. For example, the SARD compounds may treat prostate cancer andprevent metastasis. The prostate cancer may be refractory prostatecancer; advanced prostate cancer; castration resistant prostate cancer(CRPC); metastatic CRPC (mCRPC); non-metastatic CRPC (nmCRPC); orhigh-risk nmCRPC.

The SARD compounds described herein may be used to provide a dualaction. For example, the SARD compounds may treat TNBC and preventmetastasis.

Men with advanced prostate cancer who are at high risk for progressionto castration resistant prostate cancer (CRPC) are men on ADT with serumtotal testosterone concentrations greater than 20 ng/dL or men withadvanced prostate cancer who at the time of starting ADT had either (1)confirmed Gleason pattern 4 or 5 prostate cancer, (2) metastaticprostate cancer, (3) a PSA doubling time<3 months, (4) a PSA≥20 ng/mL,or (5) a PSA relapse in <3 years after definitive local therapy (radicalprostatectomy or radiation therapy).

Normal levels of prostate specific antigen (PSA) are dependent onseveral factors, such as age and the size of a male subject's prostate,among others. PSA levels in the range between 2.5-10 ng/mL areconsidered “borderline high” while levels above 10 ng/mL are considered“high.” A rate change or “PSA velocity” greater than 0.75/year isconsidered high. PSA levels may increase despite ongoing ADT or ahistory of ADT, surgical castration or despite treatment withantiandrogens and/or LHRH agonist.

Men with high risk non-metastatic castration resistant prostate cancer(high-risk nmCRPC) may include those with rapid PSA doubling times,having an expected progression-free survival of approximately 18 monthsor less (Miller K, Moul J W, Gleave M, et al. 2013. “Phase III,randomized, placebo-controlled study of once-daily oral zibotentan(ZD4054) in patients with non-metastatic castration-resistant prostatecancer,” Prostate Canc Prost Dis. February; 16:187-192). This relativelyrapid progression of their disease underscores the importance of noveltherapies for these individuals.

The methods of the invention may treat subjects with PSA levels greaterthan 8 ng/mL where the subject suffers from high-risk nmCRPC. Thepatient population includes subjects suffering from nmCRPC where PSAdoubles in less than 8 months or less than 10 months. The method mayalso treat patient populations where the total serum testosterone levelsare greater than 20 ng/mL in a subject suffering from high-risk nmCRPC.In one case, the serum free testosterone levels are greater than thoseobserved in an orchiectomized male in a subject suffering from high-risknmCRPC.

The pharmaceutical compositions of the invention may further comprise atleast one LHRH agonist or antagonist, antiandrogen, anti-programmeddeath receptor 1 (anti-PD-1) drug or anti-PD-L1 drug. LHRH agonistsinclude, but are not limited to, leuprolide acetate (Lupron®) (U.S. Pat.No. 5,480,656; U.S. Pat. Nos. 5,575,987; 5,631,020; 5,643,607;5,716,640; 5,814,342; 6,036,976 hereby incorporated by reference) or goserelin acetate (Zoladex®) (U.S. Pat. Nos. 7,118,552; 7,220,247;7,500,964 hereby incorporated by reference). LHRH antagonists include,but are not limited to, degarelix or abarelix. Antiandrogens include,but are not limited to, bicalutamide, flutamide, apalutamide,finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone,abiraterone, or any combination thereof. Anti-PD-1 drugs include, butare not limited to, AMP-224, nivolumab, pembrolizumab, pidilizumab, andAMP-554. Anti-PD-L1 drugs include, but are not limited to, BMS-936559,atezolizumab, durvalumab, avelumab, and MPDL3280A. Anti-CTLA-4 drugsinclude, but are not limited to, ipilimumab and tremelimumab.

Treatment of prostate cancer, advanced prostate cancer, CRPC, mCRPCand/or nmCRPC may result in clinically meaningful improvement inprostate cancer related symptoms, function and/or survival. Clinicallymeaningful improvement can be determined by an increase in radiographicprogression free survival (rPFS) if cancer is metastatic, or an increasemetastasis-free survival (MFS) if cancer is non-metastatic, amongothers.

The invention encompasses methods of lowering serum prostate specificantigen (PSA) levels in a male subject suffering from prostate cancer,advanced prostate cancer, metastatic prostate cancer or castrationresistant prostate cancer (CRPC) comprising administering atherapeutically effective amount of a SARD compound, wherein thecompound is represented by the structure of formulas I-IX, IA, IB, IC,ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB.

The invention encompasses a method of secondary hormonal therapy thatreduces serum PSA in a male subject suffering from castration resistantprostate cancer (CRPC) comprising administering a therapeuticallyeffective amount of a compound of formulas I-IX, IA, IB, IC, ID, IIA,IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB that reduces serum PSA in amale subject suffering from castration resistant prostate cancer.

The invention encompasses a method of reducing levels of AR, AR-fulllength (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBDmutations, AR-splice variant (AR-SV), and/or amplifications of the ARgene within the tumor in the subject in need thereof comprisingadministering a therapeutically effective amount of a compound offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXAor IXB to reduce the level of AR, AR-full length (AR-FL), AR-FL withantiandrogen resistance-conferring AR-LBD or other AR mutations,AR-splice variant (AR-SV), and/or amplifications of the AR gene withinthe tumor.

The method may increase radiographic progression free survival (rPFS) ormetastasis-free survival (MFS).

Subjects may have non-metastatic cancer; failed androgen deprivationtherapy (ADT), undergone orchidectomy, or have high or increasingprostate specific antigen (PSA) levels; subjects may be a patient withprostate cancer, advanced prostate cancer, refractory prostate cancer,CRPC patient, metastatic castration resistant prostate cancer (mCRPC)patient, or non-metastatic castration resistant prostate cancer (nmCRPC)patient. In these subjects, the refractory may be enzalutamide resistantprostate cancer. In these subjects, the nmCRPC may be high-risk nmCRPC.Further the subject may be on androgen deprivation therapy (ADT) with orwithout castrate levels of total T.

As used herein, the phrase “a subject suffering from castrationresistant prostate cancer” refers to a subject with at least one of thefollowing characteristics: has been previously treated with androgendeprivation therapy (ADT); has responded to the ADT and currently has aserum PSA>2 ng/mL or >2 ng/mL and representing a 25% increase above thenadir achieved on the ADT; a subject which despite being maintained onandrogen deprivation therapy is diagnosed to have serum PSA progression;a castrate level of serum total testosterone (<50 ng/dL) or a castratelevel of serum total testosterone (<20 ng/dL). The subject may haverising serum PSA on two successive assessments at least 2 weeks apart;been effectively treated with ADT; or has a history of serum PSAresponse after initiation of ADT.

As used herein, the term “serum PSA progression” refers to a 25% orgreater increase in serum PSA and an absolute increase of 2 ng/ml ormore from the nadir; or to serum PSA>2 ng/mL, or >2 ng/mL and a 25%increase above the nadir after the initiation of androgen deprivationtherapy (ADT). The term “nadir” refers to the lowest PSA level while apatient is undergoing ADT.

The term “serum PSA response” refers to at least one of the following:at least 90% reduction in serum PSA value prior to the initiation ofADT; to <10 ng/mL undetectable level of serum PSA (<0.2 ng/mL) at anytime; at least 50% decline from baseline in serum PSA; at least 90%decline from baseline in serum PSA; at least 30% decline from baselinein serum PSA; or at least 10% decline from baseline in serum PSA.

The methods of this invention comprise administering a combination offorms of ADT and a compound of this invention. Forms of ADT include aLHRH agonist. LHRH agonist includes, but is not limited to, leuprolideacetate (Lupron®)(U.S. Pat. No. 5,480,656; U.S. Pat. Nos. 5,575,987;5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 herebyincorporated by reference) or goserelin acetate (Zoladex®) (U.S. Pat.Nos. 7,118,552; 7,220,247; 7,500,964 hereby incorporated by reference).Forms of ADT include, but are not limited to LHRH antagonists,reversible antiandrogens, or bilateral orchidectomy. LHRH antagonistsinclude, but are not limited to, degarelix and abarelix. Antiandrogensinclude, but are not limited to, bicalutamide, flutamide, apalutamide,finasteride, dutasteride, enzalutamide, EPI-001, EPI-506, ARN-509,ODM-201, nilutamide, chlormadinone, abiraterone, or any combinationthereof.

The methods of the invention encompass administering at least onecompound of the invention and a lyase inhibitor (e.g., abiraterone).

The term “advanced prostate cancer” refers to metastatic cancer havingoriginated in the prostate, and having widely metastasized to beyond theprostate such as the surrounding tissues to include the seminal vesiclesthe pelvic lymph nodes or bone, or to other parts of the body. Prostatecancer pathologies are graded with a Gleason grading from 1 to 5 inorder of increasing malignancy. Patients with significant risk ofprogressive disease and/or death from prostate cancer should be includedin the definition and any patient with cancer outside the prostatecapsule with disease stages as low as IIB clearly has “advanced”disease. “Advanced prostate cancer” can refer to locally advancedprostate cancer. Similarly, “advanced breast cancer” refers tometastatic cancer having originated in the breast, and having widelymetastasized to beyond the breast to surrounding tissues or other partsof the body such as the liver, brain, lungs, or bone.

The term “refractory” may refer to cancers that do not respond totreatment. E.g., prostate or breast cancer may be resistant at thebeginning of treatment or it may become resistant during treatment.“Refractory cancer” may also be referred to herein as “resistantcancer”.

The term “castration resistant prostate cancer” (CRPC) refers toadvanced prostate cancer that is worsening or progressing while thepatient remains on ADT or other therapies to reduce testosterone, orprostate cancer which is considered hormone refractory, hormone naïve,androgen independent or chemical or surgical castration resistant. CRPCmay be the result of AR activation by intracrine androgen synthesis;expression of AR splice variants (AR-SV) that lack ligand binding domain(LBD); or expression of AR-LBD or other AR mutations with potential toresist antagonists. Castration resistant prostate cancer (CRPC) is anadvanced prostate cancer which developed despite ongoing ADT and/orsurgical castration. Castration resistant prostate cancer is defined asprostate cancer that continues to progress or worsen or adversely affectthe health of the patient despite prior surgical castration, continuedtreatment with gonadotropin releasing hormone agonists (e.g.,leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens(e.g., bicalutamide, flutamide, apalutamide, enzalutamide, ketoconazole,aminoglutethamide), chemotherapeutic agents (e.g., docetaxel,paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine,cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib(Iressa®), cabozantinib (Cometrig™, also known as XL184)) or otherprostate cancer therapies (e.g., vaccines (sipuleucel-T (Provenge®),GVAX, etc.), herbal (PC-SPES) and lyase inhibitor (abiraterone)) asevidenced by increasing or higher serum levels of prostate specificantigen (PSA), metastasis, bone metastasis, pain, lymph nodeinvolvement, increasing size or serum markers for tumor growth,worsening diagnostic markers of prognosis, or patient condition.

Castration resistant prostate cancer may be defined as hormone naïveprostate cancer. In men with castration resistant prostate cancer, thetumor cells may have the ability to grow in the absence of androgens(hormones that promote the development and maintenance of male sexcharacteristics).

Many early prostate cancers require androgens for growth, but advancedprostate cancers are androgen-independent, or hormone naïve.

The term “androgen deprivation therapy” (ADT) may include orchidectomy;administering luteinizing hormone-releasing hormone (LHRH) analogs;administering luteinizing hormone-releasing hormone (LHRH) antagonists;administering 5α-reductase inhibitors; administering antiandrogens;administering inhibitors of testosterone biosynthesis; administeringestrogens; or administering 17α-hydroxylase/C17, 20 lyase (CYP17A1)inhibitors. LHRH drugs lower the amount of testosterone made by thetesticles. Examples of LHRH analogs available in the United Statesinclude leuprolide (Lupron®, Viadur®, Eligard®), goserelin (Zoladex®),triptorelin (Trelstar®), and histrelin (Vantas®). Antiandrogens blockthe body's ability to use any androgens. Examples of antiandrogens drugsinclude enzalutamide (Xtandi®), flutamide (Eulexin®), apalutamide(Erleada®), bicalutamide (Casodex®), and nilutamide (Nilandron®).Luteinizing hormone-releasing hormone (LHRH) antagonists includeabarelix (Plenaxis®) or degarelix (Firmagon®) (approved for use by theFDA in 2008 to treat advanced prostate cancer). 5α-Reductase inhibitorsblock the body's ability to convert testosterone to the more activeandrogen, 5α-dihydrotestosterone (DHT) and include drugs such asfinasteride (Proscar®) and dutasteride (Avodart®). Inhibitors oftestosterone biosynthesis include drugs such as ketoconazole (Nizoral®).Estrogens include diethylstilbestrol or 17β-estradiol.17α-Hydroxylase/C17, 20 lyase (CYP17A1) inhibitors include abiraterone(Zytiga®).

The invention encompasses a method of treating antiandrogen-resistantprostate cancer. The antiandrogen may include, but is not limited to,bicalutamide, hydroxyflutamide, flutamide, apalutamide, enzalutamide orabiraterone.

The invention encompasses a method of treating prostate cancer in asubject in need thereof, wherein said subject has AR overexpressingprostate cancer, castration-resistant prostate cancer,castration-sensitive prostate cancer, AR-V7 expressing prostate cancer,or d567ES expressing prostate cancer, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof, wherein said SARD compound is represented by thestructure of formula I-IX, IA, IB, IC, ID, IIA, JIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or the compound is at least one of compounds 1001 to1064.

In one embodiment, the castration-resistant prostate cancer is ARoverexpressing castration-resistant prostate cancer, F876L mutationexpressing castration-resistant prostate cancer, F876L_T877A doublemutation expressing castration-resistant prostate cancer, AR-V7expressing castration-resistant prostate cancer, d567ES expressingcastration-resistant prostate cancer, and/or castration-resistantprostate cancer characterized by intratumoral androgen synthesis.

In one embodiment, the castration-sensitive prostate cancer is F876Lmutation expressing castration-sensitive prostate cancer, F876L_T877Adouble mutation castration-sensitive prostate cancer, and/orcastration-sensitive prostate cancer characterized by intratumoralandrogen synthesis.

In one embodiment, the treating of castration-sensitive prostate canceris conducted in a non-castrate setting, or as monotherapy, or whencastration-sensitive prostate cancer tumor is resistant to enzalutamide,apalutamide, and/or abiraterone.

The invention encompasses a method of treating AR overexpressingprostate cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a selectiveandrogen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or the compound is at least one ofcompounds 1001 to 1064.

The invention encompasses a method of treating castration-resistantprostate cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a selectiveandrogen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or the compound is at least one ofcompounds 1001 to 1064. In one embodiment, the castration-resistantprostate cancer is AR overexpressing castration-resistant prostatecancer, F876L mutation expressing castration-resistant prostate cancer,F876L_T877A double mutation expressing castration-resistant prostatecancer, AR-V7 expressing castration-resistant prostate cancer, d567ESexpressing castration-resistant prostate cancer, and/orcastration-resistant prostate cancer characterized by intratumoralandrogen synthesis.

The invention encompasses a method of treating castration-sensitiveprostate cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a selectiveandrogen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or the compound is at least one ofcompounds 1001 to 1064. In one embodiment, the castration-sensitiveprostate cancer is F876L mutation expressing castration-sensitiveprostate cancer, F876L_T877A double mutation castration-sensitiveprostate cancer, and/or castration-sensitive prostate cancercharacterized by intratumoral androgen synthesis. In one embodiment, thetreating of castration-sensitive prostate cancer is conducted in anon-castrate setting, or as monotherapy, or when castration-sensitiveprostate cancer tumor is resistant to enzalutamide, apalutamide, and/orabiraterone.

The invention encompasses a method of treating AR-V7 expressing prostatecancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a selective androgenreceptor degrader (SARD) compound, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof, wherein said SARD compound is represented by thestructure of formula I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or the compound is at least one of compounds 1001 to1064.

The invention encompasses a method of treating d567ES expressingprostate cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a selectiveandrogen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or the compound is at least one ofcompounds 1001 to 1064.

Treatment of Triple Negative Breast Cancer (TNBC)

Triple negative breast cancer (TNBC) is a type of breast cancer lackingthe expression of the estrogen receptor (ER), progesterone receptor(PR), and HER2 receptor kinase. As such, TNBC lacks the hormone andkinase therapeutic targets used to treat other types of primary breastcancers. Correspondingly, chemotherapy is often the initialpharmacotherapy for TNBC. Interestingly, AR is often still expressed inTNBC and may offer a hormone targeted therapeutic alternative tochemotherapy. In ER-positive breast cancer, AR is a positive prognosticindicator as it is believed that activation of AR limits and/or opposesthe effects of the ER in breast tissue and tumors. However, in theabsence of ER, it is possible that AR actually supports the growth ofbreast cancer tumors. Though the role of AR is not fully understood inTNBC, we have evidence that certain TNBC's may be supported by androgenindependent activation of AR-SVs lacking the LBD or androgen-dependentactivation of AR full length. As such, enzalutamide and otherLBD-directed traditional AR antagonists would not be able to antagonizeAR-SVs in these TNBC's. However, SARDs of this invention which arecapable of destroying AR-SVs (see Table 1 and Example 5) through abinding site in the NTD of AR (see Example 9) would be able toantagonize AR in these TNBC's and provide an anti-tumor effect, as shownin Example 8.

Treatment of Kennedy's Disease

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, post-polio MA ismuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain. Another type of MAis X-linked spinal-bulbar muscular atrophy (SBMA—also known as Kennedy'sDisease). This disease arises from a defect in the androgen receptorgene on the X chromosome, affects only males, and its onset is in lateadolescence to adulthood. Proximal limb and bulbar muscle weaknessresults in physical limitations including dependence on a wheelchair insome cases. The mutation results in an extended polyglutamine tract atthe N-terminal domain of the androgen receptor (polyQ AR).

Binding and activation of the polyQ AR by endogeneous androgens(testosterone and DHT) results in unfolding and nuclear translocation ofthe mutant androgen receptor. The androgen-induced toxicity andandrogen-dependent nuclear accumulation of polyQ AR protein seems to becentral to the pathogenesis. Therefore, the inhibition of theandrogen-activated polyQ AR might be a therapeutic option (A. Baniahmad.Inhibition of the androgen receptor by antiandrogens in spinobulbarmuscle atrophy. J. Mol. Neurosci. 2016 58(3), 343-347). These steps arerequired for pathogenesis and result in partial loss of transactivationfunction (i.e., an androgen insensitivity) and a poorly understoodneuromuscular degeneration. Peripheral polyQ AR anti-sense therapyrescues disease in mouse models of SBMA (Cell Reports 7, 774-784, May 8,2014). Further support of use antiandrogen comes in a report in whichthe antiandrogen flutamide protects male mice from androgen-dependenttoxicity in three models of spinal bulbar muscular atrophy (Renier K J,Troxell-Smith S M, Johansen J A, Katsuno M, Adachi H, Sobue G, Chua J P,Sun Kim H, Lieberman A P, Breedlove S M, Jordan C L. Endocrinology 2014,155(7), 2624-2634). These steps are required for pathogenesis and resultin partial loss of transactivation function (i.e., an androgeninsensitivity) and a poorly understood neuromuscular degeneration.Currently there are no disease-modifying treatments but rather onlysymptom directed treatments. Efforts to target the polyQ AR as theproximal mediator of toxicity by harnessing cellular machinery topromote its degradation hold promise for therapeutic intervention.

Selective androgen receptor degraders such as those reported herein bindto, inhibit transactivation, and degrade all androgen receptors testedto date (full length, splice variant, antiandrogen resistance mutants,etc.), indicating that they are promising leads for treatment diseaseswhose pathogenesis is androgen-dependent such as SBMA.

The invention encompasses methods of treating Kennedy's diseasecomprising administering a therapeutically effective amount of acompound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB.

As used herein, the term “androgen receptor associated conditions” or“androgen sensitive diseases or disorders” or “androgen-dependentdiseases or disorders” are conditions, diseases, or disorders that aremodulated by or whose pathogenesis is dependent upon the activity of theandrogen receptor. The androgen receptor is expressed in most tissues ofthe body however it is overexpressed in, inter alia, the prostate andskin. ADT has been the mainstay of prostate cancer treatment for manyyears, and SARDs may also be useful in treating various prostatecancers, benign prostatic hypertrophy, prostamegaly, and other maladiesof the prostate.

The invention encompasses methods of treating benign prostatichypertrophy comprising administering a therapeutically effective amountof at least one compound of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB.

The invention encompasses methods of treating prostamegaly comprisingadministering a therapeutically effective amount of at least onecompound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB.

The invention encompasses methods of treating hyperproliferativeprostatic disorders and diseases comprising administering atherapeutically effective amount of a compound of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB.

The effect of the AR on the skin is apparent in the gender dimorphismand puberty related dermatological problems common to teens and earlyadults. The hyperandrogenism of puberty stimulates terminal hair growth,sebum production, and predisposes male teens to acne, acne vulgaris,seborrhea, excess sebum, hidradenitis suppurativa, hirsutism,hypertrichosis, hyperpilosity, androgenic alopecia, male patternbaldness, and other dermatological maladies. Although antiandrogenstheoretically should prevent the hyperandrogenic dermatological diseasesdiscussed, they are limited by toxicities, sexual side effects, and lackof efficacy when topically applied. The SARDs of this invention potentlyinhibit ligand-dependent and ligand-independent AR activation, and (insome cases) have short biological half-lives in the serum, suggestingthat topically formulated SARDs of this invention could be applied tothe areas affected by acne, seborrheic dermatitis, and/or hirsutismwithout risk of systemic side effects.

The invention encompasses methods of treating acne, acne vulgaris,seborrhea, seborrheic dermatitis, hidradenitis supporativa, hirsutism,hypertrichosis, hyperpilosity, or alopecia comprising administering atherapeutically effective amount of a compound of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or any ofcompounds 1001 to 1064.

The compounds and/or compositions described herein may be used fortreating hair loss, alopecia, androgenic alopecia, alopecia areata,alopecia secondary to chemotherapy, alopecia secondary to radiationtherapy, alopecia induced by scarring or alopecia induced by stress.Generally “hair loss” or “alopecia” refers to baldness as in the verycommon type of male-pattern baldness. Baldness typically begins withpatch hair loss on the scalp and sometimes progresses to completebaldness and even loss of body hair. Hair loss affects both males andfemales.

The invention encompasses methods of treating androgenic alopeciacomprising administering a therapeutically effective amount of acompound of formula I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or any of compounds 1001 to 1064.

The invention encompasses methods of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression of ahormonal condition in a male in need thereof, comprising administeringto the subject a therapeutically effective amount of a selectiveandrogen receptor degrader (SARD) compound, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, wherein said SARD compound isrepresented by the structure of formula I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or the compound is at least one ofcompounds 1001 to 1064.

In one embodiment, the condition is hypergonadism, hypersexuality,sexual dysfunction, gynecomastia, precocious puberty in a male,alterations in cognition and mood, depression, hair loss,hyperandrogenic dermatological disorders, pre-cancerous lesions of theprostate, benign prostate hyperplasia, prostate cancer and/or otherandrogen-dependent cancers.

SARDs of this invention may also be useful in the treatment of hormonalconditions in females which can have hyperandrogenic pathogenesis suchas precocious puberty, early puberty, dysmenorrhea, amenorrhea,multilocular uterus syndrome, endometriosis, hysteromyoma, abnormaluterine bleeding, early menarche, fibrocystic breast disease, fibroidsof the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia,eclampsia of pregnancy, preterm labor, premenstrual syndrome, and/orvaginal dryness.

The invention encompasses methods of treating precocious puberty orearly puberty, dysmenorrhea or amenorrhea, multilocular uterus syndrome,endometriosis, hysteromyoma, abnormal uterine bleeding, hyper-androgenicdiseases (such as polycystic ovary syndrome (PCOS)), fibrocystic breastdisease, fibroids of the uterus, ovarian cysts, polycystic ovarysyndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor,premenstrual syndrome, or vaginal dryness comprising administering atherapeutically effective amount of a compound of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or any ofcompounds 1001 to 1064.

SARDs of this invention may also find utility in treatment of sexualperversion, hypersexuality, paraphilias, androgen psychosis,virilization, androgen insensitivity syndromes (AIS) (such as completeAIS (CAIS) and partial MS (PAIS)), and improving ovulation in an animal.

The invention encompasses methods of treating sexual perversion,hypersexuality, paraphilias, androgen psychosis, virilization androgen,insensitivity syndromes, increasing or modulating or improving ovulationcomprising administering a therapeutically effective amount of acompound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB, or any of compounds 1001 to 1064.

SARDs of this invention may also be useful for treatinghormone-dependent cancers such as prostate cancer, breast cancer,testicular cancer, ovarian cancer, hepatocellular carcinoma, urogenitalcancer, etc. In another embodiment, the breast cancer is triple negativebreast cancer. Further, local or systemic SARD administration may beuseful for treatment of precursors of hormone-dependent cancers such asprostatic intraepithelial neoplasia (PIN) and atypical small acinarproliferation (ASAP).

The invention encompasses methods of treating breast cancer, testicularcancer, uterine cancer, ovarian cancer, urogenital cancer, precursors ofprostate cancer, or AR related or AR expressing solid tumors, comprisingadministering a therapeutically effective amount of a compound offormulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXAor IXB. A precursor of prostate cancers may be prostatic intraepithelialneoplasia (PIN) or atypical small acinar proliferation (ASAP). The tumormay be hepatocellular carcinoma (HCC) or bladder cancer. Serumtestosterone may be positively linked to the development of HCC. Basedon epidemiologic, experimental observations, and notably the fact thatmen have a substantially higher risk of bladder cancer than women,androgens and/or the AR may also play a role in bladder cancerinitiation.

Although traditional antiandrogens such as enzalutamide, bicalutamideand flutamide and androgen deprivation therapies (ADT) such asleuprolide were approved for use in prostate cancer, there issignificant evidence that antiandrogens could also be used in a varietyof other hormone-dependent and hormone-independent cancers. For example,antiandrogens have been successfully tested in breast cancer(enzalutamide; Breast Cancer Res (2014) 16(1): R7), non-small cell lungcancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgeninsensitivity associated malignancies such as gonadal tumors andseminoma, advanced pancreatic cancer (World J Gastroenterology20(29):9229), cancer of the ovary, fallopian tubes, or peritoneum,cancer of the salivary gland (Head and Neck (2016) 38: 724-731; ADT wastested in AR-expressing recurrent/metastatic salivary gland cancers andwas confirmed to have benefit on progression free survival and overallsurvival endpoints), bladder cancer (Oncotarget 6 (30): 29860-29876);Int J Endocrinol (2015), Article ID 384860), pancreatic cancer, lymphoma(including mantle cell), and hepatocellular carcinoma. Use of a morepotent antiandrogen such as a SARD in these cancers may treat theprogression of these and other cancers. Other cancers may also benefitfrom SARD treatment such as testicular cancer, uterine cancer, ovariancancer, urogenital cancer, breast cancer, brain cancer, skin cancer,lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer,endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC),colon cancer, perianal adenoma, or central nervous system cancer.

SARDs of this invention may also be useful for treating other cancerscontaining AR such as breast, brain, skin, ovarian, bladder, lymphoma,liver, kidney, pancreas, endometrium, lung (e.g., NSCLC), colon,perianal adenoma, osteosarcoma, CNS, melanoma, hypercalcemia ofmalignancy and metastatic bone disease, etc.

Thus, the invention encompasses methods of treating hypercalcemia ofmalignancy, metastatic bone disease, brain cancer, skin cancer, bladdercancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreaticcancer, endometrial cancer, lung cancer, central nervous system cancer,gastric cancer, colon cancer, melanoma, amyotrophic lateral sclerosis(ALS), and/or uterine fibroids comprising administering atherapeutically effective amount of a compound of formulas I-IX, IA, IB,IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, or any ofcompounds 1001 to 1064. The lung cancer may be non-small cell lungcancer (NSCLC).

SARDs of this invention may also be useful for the treating ofnon-hormone-dependent cancers. Non-hormone-dependent cancers includeliver, salivary duct, etc.

In another embodiment, the SARDs of this invention are used for treatinggastric cancer. In another embodiment, the SARDs of this invention areused for treating salivary duct carcinoma. In another embodiment, theSARDs of this invention are used for treating bladder cancer. In anotherembodiment, the SARDs of this invention are used for treating esophagealcancer. In another embodiment, the SARDs of this invention are used fortreating pancreatic cancer. In another embodiment, the SARDs of thisinvention are used for treating colon cancer. In another embodiment, theSARDs of this invention are used for treating non-small cell lungcancer. In another embodiment, the SARDs of this invention are used fortreating renal cell carcinoma.

AR plays a role in cancer initiation in hepatocellular carcinoma (HCC).Therefore, targeting AR may be an appropriate treatment for patientswith early stage HCC. In late-stage HCC disease, there is evidence thatmetastasis is suppressed by androgens. In another embodiment, the SARDsof this invention are used for treating hepatocellular carcinoma (HCC).

Locati et al. in Head & Neck, 2016, 724-731 demonstrated the use ofandrogen deprivation therapy (ADT) in AR-expressing recurrent/metastaticsalivary gland cancers and confirmed improved progression free survivaland overall survival endpoints with ADT. In another embodiment, theSARDs of this invention are used for treating salivary gland cancer.

Kawahara et al. in Oncotarget, 2015, Vol 6 (30), 29860-29876demonstrated that ELK1 inhibition, together with AR inactivation, hasthe potential of being a therapeutic approach for bladder cancer. McBethet al. Int J Endocrinology, 2015, Vol 2015, Article ID 384860 suggestedthat the combination of antiandrogen therapy plus glucocorticoids astreatment of bladder cancer as this cancer is believed to have aninflammatory etiology. In another embodiment, the SARDs of thisinvention are used for treating bladder cancer, optionally incombination with glucocorticoids.

Abdominal Aortic Aneurysm (AAA)

An abdominal aortic aneurysm (AAA) is an enlarged area in the lower partof the aorta, the major blood vessel that supplies blood to the body.The aorta, about the thickness of a garden hose, runs from your heartthrough the center of your chest and abdomen. Because the aorta is thebody's main supplier of blood, a ruptured abdominal aortic aneurysm cancause life-threatening bleeding. Depending on the size and the rate atwhich your abdominal aortic aneurysm is growing, treatment may vary fromwatchful waiting to emergency surgery. Once an abdominal aortic aneurysmis found, doctors will closely monitor it so that surgery can be plannedif it is necessary. Emergency surgery for a ruptured abdominal aorticaneurysm can be risky. AR blockade (pharmacologic or genetic) reducesAAA. Davis et al. (Davis J P, Salmon M, Pope N H, Lu G, Su G, Meher A,Ailawadi G, Upchurch G R Jr. J Vasc Surg (2016) 63(6):1602-1612) showedthat flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated AAAinduced by porcine pancreatic elastase (0.35 U/mL) by 84.2% and 91.5%compared to vehicle (121%). Further AR −/−mice showed attenuated AAAgrowth (64.4%) compared to wildtype (both treated with elastase).Correspondingly, administration of a SARD to a patient suffering from anAAA may help reverse, treat or delay progression of AAA to the pointwhere surgery is needed.

Treatment of Wounds

Wounds and/or ulcers are normally found protruding from the skin or on amucosal surface or as a result of an infarction in an organ. A wound maybe a result of a soft tissue defect or a lesion or of an underlyingcondition. The term “wound” denotes a bodily injury with disruption ofthe normal integrity of tissue structures, sore, lesion, necrosis,and/or ulcer. The term “sore” refers to any lesion of the skin or mucousmembranes and the term “ulcer” refers to a local defect, or excavation,of the surface of an organ or tissue, which is produced by the sloughingof necrotic tissue. “Lesion” generally includes any tissue defect.“Necrosis” refers to dead tissue resulting from infection, injury,inflammation, or infarctions. All of these are encompassed by the term“wound,” which denotes any wound at any particular stage in the healingprocess including the stage before any healing has initiated or evenbefore a specific wound like a surgical incision is made (prophylactictreatment).

Examples of wounds which can be treated in accordance with the presentinvention are aseptic wounds, contused wounds, incised wounds, laceratedwounds, non-penetrating wounds (i.e. wounds in which there is nodisruption of the skin but there is injury to underlying structures),open wounds, penetrating wounds, perforating wounds, puncture wounds,septic wounds, subcutaneous wounds, etc. Examples of sores include, butare not limited to, bed sores, canker sores, chrome sores, cold sores,pressure sores, etc. Examples of ulcers include, but are not limited to,peptic ulcer, duodenal ulcer, gastric ulcer, gouty ulcer, diabeticulcer, hypertensive ischemic ulcer, stasis ulcer, ulcus cruris (venousulcer), sublingual ulcer, submucous ulcer, symptomatic ulcer, trophiculcer, tropical ulcer, veneral ulcer, e.g., caused by gonorrhoea(including urethritis, endocervicitis and proctitis). Conditions relatedto wounds or sores which may be successfully treated according to theinvention include, but are not limited to, burns, anthrax, tetanus, gasgangrene, scalatina, erysipelas, sycosis barbae, folliculitis, impetigocontagiosa, impetigo bullosa, etc. It is understood, that there may bean overlap between the use of the terms “wound” and “ulcer,” or “wound”and “sore” and, furthermore, the terms are often used at random.

The kinds of wounds to be treated according to the invention includealso: i) general wounds such as, e.g., surgical, traumatic, infectious,ischemic, thermal, chemical and bullous wounds; ii) wounds specific forthe oral cavity such as, e.g., post-extraction wounds, endodontic woundsespecially in connection with treatment of cysts and abscesses, ulcersand lesions of bacterial, viral or autoimmunological origin, mechanical,chemical, thermal, infectious and lichenoid wounds; herpes ulcers,stomatitis aphthosa, acute necrotising ulcerative gingivitis and burningmouth syndrome are specific examples; and iii) wounds on the skin suchas, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial,viral, autoimmunological), bites and surgical incisions. Another way ofclassifying wounds is by tissue loss, where: i) small tissue loss (dueto surgical incisions, minor abrasions, and minor bites) or ii)significant tissue loss. The latter group includes ischemic ulcers,pressure sores, fistulae, lacerations, severe bites, thermal burns anddonor site wounds (in soft and hard tissues) and infarctions. Otherwounds include ischemic ulcers, pressure sores, fistulae, severe bites,thermal burns, or donor site wounds.

Ischemic ulcers and pressure sores are wounds, which normally only healvery slowly and especially in such cases an improved and more rapidhealing is of great importance to the patient. Furthermore, the costsinvolved in the treatment of patients suffering from such wounds aremarkedly reduced when the healing is improved and takes place morerapidly.

Donor site wounds are wounds which e.g. occur in connection with removalof hard tissue from one part of the body to another part of the bodye.g. in connection with transplantation. The wounds resulting from suchoperations are very painful and an improved healing is therefore mostvaluable.

In one case, the wound to be treated is selected from the groupconsisting of aseptic wounds, infarctions, contused wounds, incisedwounds, lacerated wounds, non-penetrating wounds, open wounds,penetrating wounds, perforating wounds, puncture wounds, septic wounds,and subcutaneous wounds.

The invention encompasses methods of treating a subject suffering from awound comprising administering to the subject a therapeuticallyeffective amount of a compound of formulas I-IX, IA, IB, IC, ID, IIA,IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB, pharmaceutically acceptablesalt thereof, or a pharmaceutical composition thereof.

The invention encompasses methods of treating a subject suffering from aburn comprising administering to the subject a therapeutically effectiveamount of a compound of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA or IXB, pharmaceutically acceptable saltthereof, or a pharmaceutical composition thereof.

The term “skin” is used in a very broad sense embracing the epidermallayer of the skin and in those cases where the skin surface is more orless injured also the dermal layer of the skin. Apart from the stratumcorneum, the epidermal layer of the skin is the outer (epithelial) layerand the deeper connective tissue layer of the skin is called the dermis.

Since the skin is the most exposed part of the body, it is particularlysusceptible to various kinds of injuries such as, e.g., ruptures, cuts,abrasions, burns and frostbites or injuries arising from variousdiseases. Furthermore, much skin is often destroyed in accidents.However, due to the important barrier and physiologic function of theskin, the integrity of the skin is important to the well-being of theindividual, and any breach or rupture represents a threat that must bemet by the body in order to protect its continued existence.

Apart from injuries on the skin, injuries may also be present in allkinds of tissues (i.e. soft and hard tissues). Injuries on soft tissuesincluding mucosal membranes and/or skin are especially relevant inconnection with the present invention.

Healing of a wound on the skin or on a mucosal membrane undergoes aseries of stages that results either in repair or regeneration of theskin or mucosal membrane. In recent years, regeneration and repair havebeen distinguished as the two types of healing that may occur.Regeneration may be defined as a biological process whereby thearchitecture and function of lost tissue are completely renewed. Repair,on the other hand, is a biological process whereby continuity ofdisrupted tissue is restored by new tissues which do not replicate thestructure and function of the lost ones.

The majority of wounds heal through repair, meaning that the new tissueformed is structurally and chemically unlike the original tissue (scartissue). In the early stage of the tissue repair, one process which isalmost always involved is the formation of a transient connective tissuein the area of tissue injury. This process starts by formation of a newextracellular collagen matrix by fibroblasts. This new extracellularcollagen matrix is then the support for a connective tissue during thefinal healing process. The final healing is, in most tissues, a scarformation containing connective tissue. In tissues which haveregenerative properties, such as, e.g., skin and bone, the final healingincludes regeneration of the original tissue. This regenerated tissuehas frequently also some scar characteristics, e.g. a thickening of ahealed bone fracture.

Under normal circumstances, the body provides mechanisms for healinginjured skin or mucosa in order to restore the integrity of the skinbarrier or the mucosa. The repair process for even minor ruptures orwounds may take a period of time extending from hours and days to weeks.However, in ulceration, the healing can be very slow and the wound maypersist for an extended period of time, i.e. months or even years.

Burns are associated with reduced testosterone levels, and hypogonadismis associated with delayed wound healing. The invention encompassesmethods for treating a subject suffering from a wound or a burn byadministering at least one SARD compound according to this invention.The SARD may promote resolving of the burn or wound, participates in thehealing process of a burn or a wound, or, treats a secondarycomplication of a burn or wound.

The treatment of burns or wounds may further use at least one growthfactor such as epidermal growth factor (EGF), transforming growthfactor-α (TGF-α), platelet derived growth factor (PDGF), fibroblastgrowth factors (FGFs) including acidic fibroblast growth factor (α-FGF)and basic fibroblast growth factor (β-FGF), transforming growth factor-β(TGF-β) and insulin like growth factors (IGF-1 and IGF-2), or anycombination thereof, which promote wound healing.

Wound healing may be measured by many procedures known in the art,including, but not limited to, wound tensile strength, hydroxyproline orcollagen content, procollagen expression, or re-epithelialization. As anexample, a SARD as described herein may be administered orally ortopically at a dosage of about 0.1-100 mg per day. Therapeuticeffectiveness is measured as effectiveness in enhancing wound healing ascompared to the absence of the SARD compound. Enhanced wound healing maybe measured by known techniques such as decrease in healing time,increase in collagen density, increase in hydroxyproline, reduction incomplications, increase in tensile strength, and increased cellularityof scar tissue.

The term “reducing the pathogenesis” is to be understood to encompassreducing tissue damage, or organ damage associated with a particulardisease, disorder or condition. The term may include reducing theincidence or severity of an associated disease, disorder or condition,with that in question or reducing the number of associated diseases,disorders or conditions with the indicated, or symptoms associatedthereto.

Pharmaceutical Compositions

The compounds of the invention may be used in pharmaceuticalcompositions. As used herein, “pharmaceutical composition” means eitherthe compound or pharmaceutically acceptable salt of the activeingredient with a pharmaceutically acceptable carrier or diluent. A“therapeutically effective amount” as used herein refers to that amountwhich provides a therapeutic effect for a given indication andadministration regimen.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.The subjects may be a male or female subject or both.

Numerous standard references are available that describe procedures forpreparing various compositions or formulations suitable foradministration of the compounds of the invention. Examples of methods ofmaking formulations and preparations can be found in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

The mode of administration and dosage form are closely related to thetherapeutic amounts of the compounds or compositions which are desirableand efficacious for the given treatment application.

The pharmaceutical compositions of the invention can be administered toa subject by any method known to a person skilled in the art. Thesemethods include, but are not limited to, orally, parenterally,intravascularly, paracancerally, transmuco sally, transdermally,intramuscularly, intranasally, intravenously, intradermally,subcutaneously, sublingually, intraperitoneally, intraventricularly,intracranially, intravaginally, by inhalation, rectally, orintratumorally. These methods include any means in which the compositioncan be delivered to tissue (e.g., needle or catheter). Alternatively, atopical administration may be desired for application to dermal, ocular,or mucosal surfaces. Another method of administration is via aspirationor aerosol formulation. The pharmaceutical compositions may beadministered topically to body surfaces, and are thus formulated in aform suitable for topical administration. Suitable topical formulationsinclude gels, ointments, creams, lotions, drops and the like. Fortopical administrations, the compositions are prepared and applied assolutions, suspensions, or emulsions in a physiologically acceptablediluent with or without a pharmaceutical carrier.

Suitable dosage forms include, but are not limited to, oral, rectal,sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular,intravenous, transdermal, spinal, intrathecal, intra-articular,intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterileadministration, and other dosage forms for systemic delivery of activeingredients. Depending on the indication, formulations suitable for oralor topical administration are preferred.

Topical Administration:

The compounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA or IXB may be administered topically. As used herein,“topical administration” refers to application of the compounds offormulas I-IX, IA, IB, IC, ID, IIA, JIB, VIIA, VIIB, VIIIA, VIIIB, IXAor IXB (and optional carrier) directly to the skin and/or hair. Thetopical composition can be in the form of solutions, lotions, salves,creams, ointments, liposomes, sprays, gels, foams, roller sticks, andany other formulation routinely used in dermatology.

Topical administration is used for indications found on the skin, suchas hirsutism, alopecia, acne, and excess sebum. The dose will vary, butas a general guideline, the compound will be present in adermatologically acceptable carrier in an amount of from about 0.01 to50 w/w %, and more typically from about 0.1 to 10 w/w %. Typically, thedermatological preparation will be applied to the affected area from 1to 4 times daily. “Dermatologically acceptable” refers to a carrierwhich may be applied to the skin or hair, and which will allow the drugto diffuse to the site of action. More specifically “site of action”, itrefers to a site where inhibition of androgen receptor or degradation ofthe androgen receptor is desired.

The compounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA or IXB, may be used topically to relieve alopecia,especially androgenic alopecia. Androgens have a profound effect on bothhair growth and hair loss. In most body sites, such as the beard andpubic skin, androgens stimulate hair growth by prolonging the growthphase of the hair cycle (anagen) and increasing follicle size. Hairgrowth on the scalp does not require androgens but, paradoxically,androgens are necessary for the balding on the scalp in geneticallypredisposed individuals (androgenic alopecia) where there is aprogressive decline in the duration of anagen and in hair follicle size.Androgenic alopecia is also common in women where it usually presents asa diffuse hair loss rather than showing the patterning seen in men.

While the compounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA,VIIB, VIIIA, VIIIB, IXA or IXB will most typically be used to alleviateandrogenic alopecia, the compounds may be used to alleviate any type ofalopecia. Examples of non-androgenic alopecia include, but are notlimited to, alopecia areata, alopecia due to radiotherapy orchemotherapy, scarring alopecia, or stress related alopecia.

The compounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA or IXB can be applied topically to the scalp and hairto prevent, or treat balding. Further, the compound of formulas I-IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB can beapplied topically in order to induce or promote the growth or regrowthof hair on the scalp.

The invention also encompasses topically administering a compound offormula I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA orIXB to treat or prevent the growth of hair in areas where such hairgrowth in not desired. One such use will be to alleviate hirsutism.Hirsutism is excessive hair growth in areas that typically do not havehair (e.g., a female face). Such inappropriate hair growth occurs mostcommonly in women and is frequently seen at menopause. The topicaladministration of the compounds of formulas I-IX, IA, IB, IC, ID, IIA,IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB will alleviate this conditionleading to a reduction, or elimination of this inappropriate, orundesired, hair growth.

The compounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB,VIIIA, VIIIB, IXA or IXB may also be used topically to decrease sebumproduction. Sebum is composed of triglycerides, wax esters, fatty acids,sterol esters and squalene. Sebum is produced in the acinar cells of thesebaceous glands and accumulates as these cells age. At maturation, theacinar cells lyse, releasing sebum into the luminal duct so that it maybe deposited on the surface of the skin.

In some individuals, an excessive quantity of sebum is secreted onto theskin. This can have a number of adverse consequences. It can exacerbateacne, since sebum is the primary food source for Propionbacterium acnes,the causative agent of acne. It can cause the skin to have a greasyappearance, typically considered cosmetically unappealing.

Formation of sebum is regulated by growth factors and a variety ofhormones including androgens. The cellular and molecular mechanism bywhich androgens exert their influence on the sebaceous gland has notbeen fully elucidated. However, clinical experience documents the impactandrogens have on sebum production. Sebum production is significantlyincreased during puberty, when androgen levels are their highest. Thecompounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA,VIIIB, IXA or IXB inhibit the secretion of sebum and thus reduce theamount of sebum on the surface of the skin. The compounds of formulasI-IX, IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB canbe used to treat a variety of dermal diseases such as acne or seborrheicdermatitis.

In addition to treating diseases associated with excess sebumproduction, the compounds of formulas I-IX, IA, IB, IC, ID, IIA, IIB,VIIA, VIIB, VIIIA, VIIIB, IXA or IXB can also be used to achieve acosmetic effect. Some consumers believe that they are afflicted withoveractive sebaceous glands. They feel that their skin is oily and thusunattractive. These individuals may use the compounds of formulas I-IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB todecrease the amount of sebum on their skin. Decreasing the secretion ofsebum will alleviate oily skin in individuals afflicted with suchconditions.

To treat these topical indications, the invention encompasses cosmeticor pharmaceutical compositions (such as dermatological compositions),comprising at least one of the compounds of formulas I-IX, IA, IB, IC,ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB. Such dermatologicalcompositions will contain from 0.001% to 10% w/w % of the compound(s) inadmixture with a dermatologically acceptable carrier, and moretypically, from 0.1 to 5 w/w % of the compounds. Such compositions willtypically be applied from 1 to 4 times daily. The reader's attention isdirected to Remington's Pharmaceutical Science, Edition 17, MarkPublishing Co., Easton, Pa. for a discussion of how to prepare suchformulations.

The compositions of the invention may also include solid preparationssuch as cleansing soaps or bars. These compositions are preparedaccording to methods known in the art.

Formulations such as aqueous, alcoholic, or aqueous-alcoholic solutions,or creams, gels, emulsions or mousses, or aerosol compositions with apropellant may be used to treat indications that arise where hair ispresent. Thus, the composition can also be a hair care composition. Suchhair care compositions include, but are not limited to, shampoo, ahair-setting lotion, a treating lotion, a styling cream or gel, a dyecomposition, or a lotion or gel for preventing hair loss. The amounts ofthe various constituents in the dermatological compositions are thoseconventionally used in the fields considered.

Medicinal and cosmetic agents containing the compounds of formulas I-IX,IA, IB, IC, ID, IIA, IIB, VIIA, VIIB, VIIIA, VIIIB, IXA or IXB willtypically be packaged for retail distribution (i.e., an article ofmanufacture). Such articles will be labeled and packaged in a manner toinstruct the patient how to use the product. Such instructions willinclude the condition to be treated, duration of treatment, dosingschedule, etc.

Antiandrogens, such as finasteride or flutamide, have been shown todecrease androgen levels or block androgen action in the skin to someextent but suffer from undesirable systemic effects. An alternativeapproach is to topically apply a selective androgen receptor degrader(SARD) compound to the affected areas. Such SARD compound would exhibitpotent but local inhibition of AR activity, and local degradation of theAR, would not penetrate to the systemic circulation of the subject, orwould be rapidly metabolized upon entry into the blood, limitingsystemic exposure.

To prepare such pharmaceutical dosage forms, the active ingredient maybe mixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration.

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

Oral and Parenteral Administration:

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, suspensions, elixirs, and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, coloring agents, and the like. For solid oralpreparations such as, powders, capsules, and tablets, suitable carriersand additives include starches, sugars, diluents, granulating agents,lubricants, binders, disintegrating agents, and the like. Due to theirease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form. If desired, tablets may be sugarcoated or enteric coated by standard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater, though other ingredients may be included, such as ingredientsthat aid solubility or for preservation. Injectable solutions may alsobe prepared in which case appropriate stabilizing agents may beemployed.

In some applications, it may be advantageous to utilize the active agentin a “vectorized” form, such as by encapsulation of the active agent ina liposome or other encapsulant medium, or by fixation of the activeagent, e.g., by covalent bonding, chelation, or associativecoordination, on a suitable biomolecule, such as those selected fromproteins, lipoproteins, glycoproteins, and polysaccharides.

Methods of treatment using formulations suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets,or lozenges, each containing a predetermined amount of the activeingredient. Optionally, a suspension in an aqueous liquor or anon-aqueous liquid may be employed, such as a syrup, an elixir, anemulsion, or a draught.

A tablet may be made by compression or molding, or wet granulation,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine, with the activecompound being in a free-flowing form such as a powder or granules whichoptionally is mixed with, for example, a binder, disintegrant,lubricant, inert diluent, surface active agent, or discharging agent.Molded tablets comprised of a mixture of the powdered active compoundwith a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavorings, suitable preservative, agents to retardcrystallization of the sugar, and agents to increase the solubility ofany other ingredient, such as a polyhydroxy alcohol, for exampleglycerol or sorbitol.

Formulations suitable for parenteral administration may comprise asterile aqueous preparation of the active compound, which preferably isisotonic with the blood of the recipient (e.g., physiological salinesolution). Such formulations may include suspending agents andthickening agents and liposomes or other microparticulate systems whichare designed to target the compound to blood components or one or moreorgans. The formulations may be presented in unit-dose or multi-doseform.

Parenteral administration may comprise any suitable form of systemicdelivery. Administration may for example be intravenous, intra-arterial,intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal(e.g., intraperitoneal), etc., and may be effected by infusion pumps(external or implantable) or any other suitable means appropriate to thedesired administration modality.

Nasal and other mucosal spray formulations (e.g. inhalable forms) cancomprise purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations arepreferably adjusted to a pH and isotonic state compatible with the nasalor other mucous membranes. Alternatively, they can be in the form offinely divided solid powders suspended in a gas carrier. Suchformulations may be delivered by any suitable means or method, e.g., bynebulizer, atomizer, metered dose inhaler, or the like.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acids.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more ingredient selected fromdiluents, buffers, flavoring agents, binders, disintegrants, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants), and the like.

The formulations may be of immediate release, sustained release,delayed-onset release or any other release profile known to one skilledin the art.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight, genetics and/or response of the particularindividual.

The methods of the invention comprise administration of a compound at atherapeutically effective amount. The therapeutically effective amountmay include various dosages.

In one embodiment, a compound of this invention is administered at adosage of 1-3000 mg per day. In additional embodiments, a compound ofthis invention is administered at a dose of 1-10 mg per day, 3-26 mg perday, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg perday, 15-60 mg, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day,125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg perday, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day,1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day,2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of25 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 40 mg per day. In one embodiment, a compoundof this invention is administered at a dosage of 50 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of67.5 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 75 mg per day. In one embodiment, a compoundof this invention is administered at a dosage of 80 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of100 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 125 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 250 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 300 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of600 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 1000 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 1500 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 2000 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 2500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of3000 mg per day.

The methods may comprise administering a compound at various dosages.For example, the compound may be administered at a dosage of 3 mg, 10mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg,300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500mg or 3000 mg.

Alternatively, the compound may be administered at a dosage of 0.1mg/kg/day. The compound may administered at a dosage between 0.2 to 30mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100mg/kg/day.

The pharmaceutical composition may be a solid dosage form, a solution,or a transdermal patch. Solid dosage forms include, but are not limitedto, tablets and capsules.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Synthesis of SARDs Synthesis of Intermediates 9-10

(2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2)

D-Proline (1, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath. The resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The temperature of the mixture was kept at 10-11° C. during the additionof the methacryloyl chloride. After stirring (3 hours (h), roomtemperature (RT)), the mixture was evaporated in vacuo at a temperatureof 35-45° C. to remove acetone. The resulting solution was washed withethyl ether and was acidified to pH 2 with concentrated HCl. The acidicmixture was saturated with NaCl and was extracted with EtOAc (100 mL×3).The combined extracts were dried over Na₂SO₄, filtered through Celite®,and evaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C. (lit. mp 102.5-103.5° C.); the NMR spectrum of this compounddemonstrated the existence of two rotamers of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer,5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for bothrotamers, vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) forthe second rotamer (totally 1H for both rotamers, CH at the chiralcenter), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H,CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3,169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437(OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178cm⁻¹; [α]_(D) ²⁶+80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C, 59.00,H, 7.15, N, 7.65. Found: C, 59.13, H, 7.19, N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione(3)

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at RT, and the resultingmixture was stirred 3 days. The solvent was removed in vacuo, and ayellow solid was precipitated. The solid was suspended in water, stirredovernight at RT, filtered, and dried to give 18.6 g (81%) (smallerweight when dried ˜34%) of the titled compound as a yellow solid: mp158.1-160.3° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at thechiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d, J=11.4 Hz,1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH), 2.04-1.72(m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474,1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm⁻¹;[α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. for C₉H₁₂BrNO₃: C,41.24, H, 4.61, N, 5.34. Found: C, 41.46, H, 4.64, N, 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4)

A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite®, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 110.3-113.8° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d,J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500(COOH), 1730 (C═O), 1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D)²⁶+10.5° (c=2.6, MeOH); Anal. Calcd. for C₄H₇BrO₃: C, 26.25, H, 3.86.Found: C, 26.28, H, 3.75.

(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8)

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (4, 51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere.The resulting mixture was stirred for 3 h under the same condition. Tothis was added Et₃N (39.14 g, 0.39 mol) and stirred for 20 min under thesame condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (6, 40.0g, 0.21 mol), 400 mL of THF were added and then the mixture was allowedto stir overnight at RT. The solvent was removed under reduced pressureto give a solid which was treated with 300 mL of H₂O, and extracted withEtOAc (2×400 mL). The combined organic extracts were washed withsaturated NaHCO₃ solution (2×300 mL) and brine (300 mL). The organiclayer was dried over MgSO₄ and concentrated under reduced pressure togive a solid which was purified from column chromatography usingCH₂Cl₂/EtOAc (80:20) to give a solid. This solid was recrystallized fromCH₂Cl₂/hexane to give 55.8 g (73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamideas a light-yellow solid.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). MS (ESI) 349.0 [M−H]⁻; mp 124-126° C.

(2R)-3-Bromo-N-(4-cyano-3-chlorophenyl)-2-hydroxy-2-methylpropanamide(7)

Under an argon atmosphere, thionyl chloride (15 mL, 0.20 mol) was addeddropwise to a cooled solution (less than 4° C.) of(R)-3-bromo-2-hydroxy-2-methylpropanoic acid (4, 24.3 g, 0.133 mol) in300 mL of THF at ice-water bath. The resulting mixture stirred for 3 hunder the same condition. To this was added Et₃N (35 mL, 0.245 mol) andstirred for 20 min under the same condition. After 20 min, a solution of4-amino-2-chlorobenzonitrile (5, 15.6 g, 0.10 mol) in 100 mL of THF wereadded and then the mixture was allowed to stir overnight at RT. Thesolvent removed under reduced pressure to give a solid, which treatedwith 300 mL of H₂O, and extracted with EtOAc (2×150 mL). The combinedorganic extracts washed with saturated NaHCO₃ solution (2×150 mL) andbrine (300 mL). The organic layer was dried over MgSO₄ and concentratedunder reduced pressure to give a solid, which purified by flash columnchromatography using CH₂Cl₂/EtOAc (80:20) to give a solid. This solidwas recrystallized from CH₂Cl₂/hexane to give 31.8 g (73%) of(2R)-3-bromo-N-(4-cyano-3-chlorophenyl)-2-hydroxy-2-methylpropanamide(7) as a light-yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 1.7 (s, 3H, CH₃), 3.0 (s, 1H, OH), 3.7 (d, 1H,CH), 4.0 (d, 1H, CH), 7.5 (d, 1H, ArH), 7.7 (d, 1H, ArH), 8.0 (s, 1H,ArH), 8.8 (s, 1H, NH). MS: 342 (M+23); mp 129° C.

(S)—N-(3-Chloro-4-cyanophenyl)-2-methyloxirane-2-carboxamide (9)

A mixture of3-bromo-N-(4-cyano-3-chlorophenyl)-2-hydroxy-2-methylpropanamide (7,0.84 mmol) and potassium carbonate (1.68 mmol) in 10 mL acetone washeated to reflux for 30 min. After complete conversion of startingbromide 7 to desired epoxide 9 as monitored by TLC, the solvent wasevaporated under reduced pressure to give yellowish residue, which waspoured into 10 mL of anhydrous EtOAc. The solution was filtered throughCelite® pad to remove K₂CO₃ residue and condensed under reduced pressureto give epoxide 9 as a light yellowish solid.

¹H NMR (CDCl₃, 400 MHz) δ 8.41 (bs, NH), 8.02 (d, J=2.0 Hz, 1H, ArH),7.91 (dd, J=2.0, 8.4 Hz, 1H, ArH), 7.79 (d, J=2.0 Hz, 1H, ArH), 3.01 (s,2H), 1.69 (s, 3H). MS (ESI) m/z 235.0 [M−H]⁻.

5-Membered Ring Compounds

Five membered ring compounds of the invention were made using thefollowing general synthetic routes (Method A and Method B) where m=0.Variables X and Y are defined as necessary to obtain the desiredcompound.

Method A:

Preparation of lithium diisopropylamide (LDA) solution in THF: To astirred solution of freshly distilled diisopropylamine (0.14 mL, 1.2mmol) in anhydrous 5 mL of THF was added a solution of n-butyllithium(0.53 mL, 1.32 mmol, 2.5 M solution in hexane) at −78° C. under argonatmosphere. The prepared solution of LDA or commercial 2.0 M LDA wasslowly warmed to 0° C. and stirred for 10 min and cooled again to −78°C. To the LDA solution was added dropwise a solution of 9′ (1.0 mmol) in5 mL of THF for 20 min. Compound 7 or 8 in THF was added dropwisethrough dropping funnel under argon atmosphere at −78° C. The reactionmixture was stirred at the same temperature for 30 min and quenched byaddition of sat. NH₄Cl. The solution was concentrated under reducedpressure and dispersed into excess EtOAc and dried over Na₂SO₄. Thesolution was concentrated and the resulting solid was recrystallizedfrom EtOAc/hexane or DCM/hexane to give designed compound 10′. Themother liquor was concentrated and purified by flash columnchromatography (EtOAc/hexane) to give a second crop of 10′.

Method B:

The steps through the synthesis of the oxiranes 9 and 10 are the same asabove for Scheme 1. NaH of 60% dispersion in mineral oil (228 mg, 5.7mmol) was added in 20 mL of anhydrous THF solvent into a 100 mL driedtwo necked round bottom flask equipped with a dropping funnel. Acompound of general structure 12′ (2.84 mmol) was added to the solutionunder argon atmosphere in ice-water bath, and the resulting solution wasstirred for 30 min at the ice-water bath. Into the flask, epoxide 9 or10 (2.84 mmol in THF) was added through dropping funnel under argonatmosphere at the ice-water bath and stirred overnight at RT. Afteradding 1 mL of H₂O, the reaction mixture was condensed under reducedpressure, and then dispersed into 50 mL of EtOAc, washed with 50 mL (×2)water, brine, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography with an eluent ofEtOAc/hexane, and the condensed compounds were then recrystallized inEtOAc/hexane to give a product of general structure 13′.

The synthetic procedure for 1001 as an example:

(S)-3-(3-Cyano-1H-pyrrol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₇H₁₃F₃N₄O₂) (1001)

To a solution of 1H-pyrrole-3-carbonitrile (0.10 g, 0.00108 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.090g, 0.00217 mol). After addition, the resulting mixture was stirred for 3h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 0.38 g, 0.00108 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:1) as eluent to afford 0.26 gof the titled compound as pinkish solid.

Compound 1001 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.44 (s, 1H, NH), 8.44 (s, 1H, ArH), 8.24 (d, J=8.8 Hz, 1H, ArH), 8.10(d, J=8.8 Hz, 1H, ArH), 7.49 (s, 1H, Pyrrole-H), 6.38 (t, J=2.0 Hz, 1H,Pyrrole-H), 6.41-6.40 (m, 2H, OH and Pyrrole-H), 4.30 (d, J=14.0 Hz, 1H,CH), 4.14 (d, J=14.0 Hz, 1H, CH), 1.34 (s, 3H, CH₃); (ESI, Positive):363.1079[M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂F₄N₄O₂) (1002)

To a solution of 4-fluoro-pyrazole (0.10 g, 0.00116 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.12 g,0.00291 mol). After addition, the resulting mixture was stirred for 3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8) (0.41 g, 0.00116 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using ethyl acetate and hexanes (1:1) as eluent toafford 0.13 g of the titled compound as white solid.

Compound 1002 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.39 (s, 1H, NH), 8.47 (d, J=1.6 Hz, 1H, ArH), 8.24 (dd, J=8.4 Hz,J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.73 (d, J=4.4 Hz, 1H,Pyrazole-H), 7.41 (d, J=4.4 Hz, 1H, Pyrazole-H), 6.31 (s, 1H, OH), 4.38(d, J=14.0 Hz, 1H, CH), 4.21 (d, J=14.0 Hz, 1H, CH), 1.34 (s, 3H, CH₃);Mass (ESI, Positive): 357.0966[M+H]⁺; mp 109-111° C.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamidehydrochloride (C₁₅H₁₃ClF₄N₄O₂) (1002-HCl)

To a solution of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(0.100 g, 0.2807 mmol) in 3 mL of methanol was added hydrochloride (2 MHCl in ether, 0.15 mL, 0.2947 mol). After addition, the resultingmixture was stirred for 1-2 h at RT. Solvent was removed under vacuum,and dried to afford 0.11 g (99%) of the titled compound as white foam.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamideoxalate (C₁₇H₁₄F₄N₄O₆) (1002-oxalic acid salt)

To a solution of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(0.050 g, 0.14034 mmol) in 2 mL of methanol was added oxalic acid(0.0177 g, 0.14034 mol). After addition, the resulting mixture wasstirred for 1-2 h at RT. Diethyl ether was added to above solution, andthe solid was filtered, and dried under vacuum to afford 0.058 g (92%)of the titled compound as white solid.

Compound 1002-oxalate was characterized as follows: ¹H NMR (400 MHz,DMSO-d₆) δ 14.02 (bs, 2H), 10.38 (s, 1H, NH), 8.46 (s, 1H, ArH), 8.24(d, J=8.4 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.73 (d, J=4.8 Hz,1H, Pyrazole-H), 7.41 (d, J=4.0 Hz, 1H, Pyrazole-H), 6.30 (s, 1H, OH),4.38 (d, J=14.0 Hz, 1H, CH), 4.31 (s, 2H), 4.21 (d, J=14.0 Hz, 1H, CH),2.42 (s, 4H), 1.34 (s, 3H, CH₃).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide2,3-dihydroxysuccinate (C₁₉H₁₈F₄N₄O₈) (1002-tartaric acid salt)

To a solution of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(0.050 g, 0.14034 mmol) in 2 mL of methanol was added L-(+)-tartaricacid (0.021 g, 0.14034 mol). After addition, the resulting mixture wasstirred for 1-2 h at RT. Diethyl ether was added to above solution, andthe solid was filtered and dried under vacuum to afford 0.067 g (94%) ofthe titled compound as white solid.

Compound 1002—tartaric acid salt was characterized as follows: ¹H NMR(400 MHz, DMSO-d₆) δ 12.69 (s, 2H), 10.38 (s, 1H, NH), 8.46 (s, 1H,ArH), 8.24 (d, J=8.4 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.73 (d,J=4.4 Hz, 1H, Pyrazole-H), 7.41 (d, J=4.0 Hz, 1H, Pyrazole-H), 6.30 (s,1H, OH), 5.08 (s, 2H, OH), 4.38 (d, J=14.0 Hz, 1H, CH), 4.31 (s, 2H),4.21 (d, J=14.0 Hz, 1H, CH), 2.42 (s, 4H), 1.34 (s, 3H, CH₃).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamidehydrobromide (C₁₅H₁₃BrF₄N₄O₂) (1002-HBr)

To a solution of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(0.050 g, 0.1403 mmol) in 2 mL of methanol was added hydrobromide (48%w/w aqueous solution, 0.0159 mL, 0.1403 mol). After addition, theresulting mixture was stirred for 1-2 h at RT. Solvent was removed undervacuum, and dried to afford 0.061 g (99%) of the titled compound asyellowish foam.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamidesuccinate (1002-succinic acid salt) (C₁₉H₁₈F₄N₄O₆)

To a solution of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(0.050 g, 0.14034 mmol) in 2 mL of methanol was added succinic acid(0.0166 g, 0.14034 mol). After addition, the resulting mixture wasstirred for 1-2 h at RT. Diethyl ether was added to above solution, andthe solid was filtered and dried under vacuum to afford 0.063 g (95%) ofthe titled compound as white solid.

Compound 1002—tartaric acid salt was characterized as follows: ¹H NMR(400 MHz, DMSO-d₆) δ 12.14 (s, 2H), 10.39 (s, 1H, NH), 8.46 (s, 1H,ArH), 8.24 (d, J=8.8 Hz, 1H, ArH), 8.10 (d, J=8.8 Hz, 1H, ArH), 7.73 (d,J=4.4 Hz, 1H, Pyrazole-H), 7.41 (d, J=4.4 Hz, 1H, Pyrazole-H), 6.30 (s,1H, OH), 4.39 (d, J=14.0 Hz, 1H, CH), 4.21 (d, J=14.0 Hz, 1H, CH), 2.42(s, 4H), 1.34 (s, 3H, CH₃).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-phenyl-1H-pyrazol-1-yl)propanamide(C₂₁H₁₇F₃N₄O₂) (1003)

To a solution of 4-phenyl-pyrazole (0.50 g, 0.003468 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil (0.35 g,0.00867 mol). After addition, the resulting mixture was stirred for 3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 1.22 g, 0.003468 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2) as eluent to afford 0.90 gof the titled compound as white needles.

Compound 1003 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.40 (s, 1H, NH), 8.46 (d, J=2.0 Hz, 1H, ArH), 8.24 (dd, J=8.4 Hz,J=2.0 Hz, 1H, ArH), 8.09 (d, J=8.4 Hz, 1H, ArH), 8.05 (s, 1H,Pyrazole-H), 7.82 (s, 1H, Pyrazole-H), 7.52-7.45 (m, 2H, ArH), 7.35-7.31(m, 2H, ArH), 7.20-7.16 (m, 1H, ArH), 6.33 (s, 1H, OH), 4.50 (d, J=14.0Hz, 1H, CH), 4.30 (d, J=14.0 Hz, 1H, CH), 1.40 (s, 3H, CH₃); Mass (ESI,Positive): 415.1455[M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(3-phenyl-1H-pyrrol-1-yl)propanamide(C₂₂H₁₈F₃N₃O₂) (1004)

To a solution of 3-phenyl-pyrrole (0.50 g, 0.00349 mol) in anhydrous THF(10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.35 g,0.00873 mol). After addition, the resulting mixture was stirred for 3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 1.23 g, 0.00349 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2) as eluent to afford 0.90 gof the titled compound as pink solid.

Compound 1004 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.41 (s, 1H, NH), 8.24 (d, J=1.6 Hz, 1H, ArH), 8.17 (dd, J=8.4 Hz,J=2.0 Hz, 1H, ArH), 8.07 (d, J=8.4 Hz, 1H, ArH), 7.38-7.33 (m, 4H, ArH),7.28-7.24 (m, 1H, ArH), 6.96 (t, J=3.0 Hz, 1H, Pyrrole-H), 6.28 (s, 1H,OH), 6.07 (t, J=3.5 Hz, 1H, Pyrrole-H), 6.03 (m, 1H, Pyrrole-H),4.30-4.22 (m, 2H, CH₂), 1.01 (s, 3H, CH₃); Mass (ESI, Positive):414.1432[M+H]⁺.

Bromo-1H-imidazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamides(1005 and 1006)

Lithium diisopropylamide solution (2.0 M) in THF/heptane/ethylbenzene (1mL) was slowly added to a solution of 4-bromo-1H-imidazole (1.0 mmol, 2mmol) in 5 mL of anhydrous THF at −78° C. and warmed to 0° C. andstirred for 10 min and cooled again to −78° C. To the solution was addeddropwise a solution of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(10, 1 mmol) prepared from 8 (1 mmol) and the reaction mixture wasstirred for overnight. After quenching by addition of sat. NH₄Cl, thesolution was concentrated under reduced pressure and dispersed intoexcess EtOAc and dried over Na₂SO₄. The solution was concentrated andpurified by flash column chromatography (EtOAc/hexane) to give thedesired products as total yield of 69% (37% for 1005 and 32% for 1006)as white solids.

The compounds were characterized as follows:

(S)-3-(5-Bromo-1H-imidazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂BrF₃N₄O₂) (1005)

Method A (using bromoamide 8 and 4-bromo-1H-imidazole instead of generalstructure 9′) gave a white solid; ¹H NMR (acetone-d₆, 400 MHz) δ 9.93(bs, 1H, NH), 8.44 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.6, 2.0 Hz, 1H), 8.03(d, J=8.6 Hz, 1H), 7.47 (s, 1H), 7.11 (s, 1H), 5.83 (s, 1H, OH), 4.50(d, J=14.0 Hz, 1H), 4.23 (d, J=14.0 Hz, 1H), 1.55 (s, 3H); ¹⁹F NMR(acetone-d₆, 400 MHz) δ 114.69; MS (ESI): 415.0 [M−H]⁻; LCMS (ESI) m/zcalcd for C₁₅H₁₁N₄O₂F₃Br: 415.0088. Found: 415.0017 [M−H]⁻.

(S)-3-(4-Bromo-1H-imidazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂BrF₃N₄O₂) (1006)

Method A (using bromoamide 8 and 4-bromo-1H-imidazole instead of generalstructure 9′) gave a white solid; ¹H NMR (CDCl₃, 400 MHz) δ 9.48 (bs,1H, NH), 8.15 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H),7.71 (s, 1H), 6.75 (s, 1H), 4.53 (d, J=14.4 Hz, 1H), 4.09 (d, J=14.4 Hz,1H), 2.84 (s, 1H, OH), 1.45 (s, 3H); ¹⁹F NMR (CDCl₃, 400 MHz) δ-62.19;MS (ESI): 415.0 [M−H]⁻.

(S)—N-(3-Chloro-4-cyanophenyl)-2-hydroxy-3-(1H-imidazol-1-yl)-2-methylpropanamide(C₁₄H₁₃ClN₄O₂) (1008)

Method A (using bromoamide 7 and 1H-imidazole instead of generalstructure 9′) gave a yellowish solid. Yield 53%; ¹H NMR (DMSO-d₆, 400MHz) δ 10.24 (bs, 1H, NH), 8.19 (s, 1H), 7.90 (m, 2H), 7.53 (s, 1H),7.05 (s, 1H), 6.83 (s, 1H), 6.40 (bs, 1H, OH), 4.31 (d, J=14.4 Hz, 1H),4.11 (d, J=14.4 Hz, 1H), 1.34 (s, 3H); LCMS (ESI) m/z calcd forC₁₄H₁₄ClN₄O₂: 305.0805.

Found: 305.0809 [M+H]⁺.

(S)—N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-methyl-3-(pyrrolidin-1-yl)propanamide(C₁₅H₁₈ClN₃O₂) (1009)

Method A (using bromoamide 7 and pyrrolidine instead of generalstructure 9′) gave a yield of 89%; ¹H NMR (CDCl₃, 400 MHz) δ 9.41 (bs,1H, NH), 7.98 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.51 (dd,J=8.8, 2.0 Hz, 1H), 5.20 (s, 1H), 3.15 (d, J=12.4 Hz, 1H), 2.72 (d,J=12.4 Hz, 1H), 2.64-2.58 (m, 4H), 1.76 (m, 4H), 1.41 (s, 3H); ¹³C NMR(CDCl₃, 100 MHz) δ 175.6 (—NHCO—), 142.5, 137.9, 134.6, 119.9, 117.3,116.1, 108.0, 72.9, 62.3, 54.6 (2C), 25.5, 24.0; LCMS (ESI) m/z calcdfor C₁₅H₁₉ClN₃O₂: 308.1166. Found: 308.1173 [M+H]⁺.

Preparation of HCl salt type of(S)—N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methyl-3-(pyrrolidin-1-yl)propanamide

To a solution of 1009 in EtOH (20 mL) was added dropwise acetyl chloride(1 mL) at 0° C. and further stirred at RT overnight and removed thesolvent to gain target salt of 1009.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₄H₁₂ClFN₄O₂) (1007)

Method B (using oxirane 9 and 4-fluoro-1H-pyrazole instead of generalstructure 12′) gave a yellowish solid; yield 72%; ¹H NMR (CDCl₃, 400MHz) δ 8.97 (bs, 1H, NH), 7.88 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz,1H), 7.45 (dd, J=8.4, 2.0 Hz, 1H), 7.36 (d, J=4.0 Hz, 1H), 7.35 (d,J=4.4 Hz, 1H), 5.86 (bs, 1H, OH), 4.54 (d, J=14.0 Hz, 1H), 4.15 (d,J=14.0 Hz, 1H), 1.46 (s, 3H); ¹⁹F NMR (CDCl₃, 400 MHz) δ-176.47; LCMS(ESI) m/z calcd for C₁₄H₁₃ClFN₄O₂: 323.0711.

Found: 323.0710 [M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-(4-fluorophenyl)-1H-pyrrol-1-yl)-2-hydroxy-2-methylpropanamide(C₂₂H₁₇F₄N₃O₂) (1010)

To a solution of 3-(4-fluorophenyl)-pyrrole (0.50 g, 0.003102 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.37g, 0.009306 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8) (1.09 g, 0.003102 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using ethyl acetate and hexanes (1:2 to 1:1) as eluentto afford 0.60 g (45%) of the compound as yellowish solid.

Compound 1010 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.40 (s, 1H, NH), 8.42 (d, J=2.0 Hz, 1H, ArH), 8.24 (dd, J=8.8 Hz,J=2.0 Hz, 1H, ArH), 8.07 (d, J=8.8 Hz, 1H, ArH), 7.43-7.38 (m, 2H, ArH),7.11-7.05 (m, 3H, ArH), 6.73 (t, J=2.0 Hz, 1H, Pyrrole-H), 6.33 (s, 1H,OH), 4.24 (d, J=14.0 Hz, 1H, CH), 4.05 (d, J=14.0 Hz, 1H, CH), 1.37 (s,3H, CH₃); Mass (ESI, Positive): 432.1352[M+H]⁺; mp 187-189° C.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(3-phenyl-1H-pyrazol-1-yl)propanamide(C₂₁H₁₇F₃N₄O₂) (1011)

To a solution of 3-phenyl-pyrazole (0.50 g, 0.003468 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.35 g,0.00867 mol). After addition, the resulting mixture was stirred for 3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 1.22 g, 0.003468 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:3 to 1:2) as eluent to afford0.60 g of the titled compound as white needles.

Compound 1011 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.33 (s, 1H, NH), 8.48 (d, J=2.0 Hz, 1H, ArH), 8.22 (dd, J=8.2 Hz,J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.2 Hz, 1H, ArH), 7.69 (d, J=2.0 Hz, 1H,ArH), 7.60-7.57 (m, 2H, ArH), 7.28-7.21 (m, 3H, ArH), 6.66 (d, J=3.0 Hz,1H, ArH), 6.31 (s, 1H, OH), 4.52 (d, J=14.6 Hz, 1H, CH), 4.32 (d, J=14.6Hz, 1H, CH), 1.43 (s, 3H, CH₃).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂F₄N₄O₂) (1012)

To a solution of 3-fluoro-pyrazole (0.20 g, 0.00232 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.24 g,0.00582 mol). After addition, the resulting mixture was stirred for 3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 0.82 g, 0.00232 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (2:1) as eluent to afford 0.36 gof the compound as white needles.

Compound 1012 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.39 (s, 1H, NH), 8.47 (d, J=2.0 Hz, 1H, ArH), 8.24 (dd, J=8.8 Hz,J=2.0 Hz, 1H, ArH), 8.11 (d, J=8.8 Hz, 1H, ArH), 7.55 (t, J=3.0 Hz, 1H,Pyrazole-H), 6.29 (s, 1H, OH), 5.93-5.91 (m, 1H, Pyrazole-H), 4.34 (d,J=13.6 Hz, 1H, CH), 4.15 (d, J=13.6 Hz, 1H, CH), 1.36 (s, 3H, CH₃); Mass(ESI, Positive): 357.0966 [M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(1H-pyrazol-1-yl)propanamide(C₁₅H₁₃F₃N₄O₂) (1013)

To a solution of 1H-pyrazole (0.20 g, 0.002938 mol) in anhydrous THF (10mL), which was cooled in an ice water bath under an argon atmosphere,was added sodium hydride (60% dispersion in oil, 0.29 g, 0.007344 mol).After addition, the resulting mixture was stirred for 3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 1.03 g, 0.002938 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (2:1) as eluent to afford 0.52 gof the compound as white solid.

Compound 1013 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.39 (s, 1H, NH), 8.48 (d, J=2.0 Hz, 1H, ArH), 8.22 (dd, J=8.2 Hz,J=2.0 Hz, 1H, ArH), 8.08 (d, J=8.2 Hz, 1H, ArH), 7.66-7.65 (m, 1H,Pyrazole-H), 7.39-7.38 (m, 1H, Pyrazole-H), 6.28 (s, 1H, OH), 6.25-6.23(m, 1H, Pyrazole-H), 4.50 (d, J=13.6 Hz, 1H, CH), 4.29 (d, J=13.6 Hz,1H, CH), 1.35 (s, 3H, CH₃); Mass (ESI, Positive): 339.1105 [M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide(C₁₆H₁₂F₆N₄O₂) (1014)

To a solution of 3-trifluoromethyl-pyrazole (0.20 g, 0.00147 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.15g, 0.003674 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8) (0.516 g, 0.00147 mol) was added to above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using ethyl acetate and hexanes (2:1) as eluent toafford the titled compound (103 mg, 70%) as a white solid.

Compound 1014 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.31 (bs, 1H, NH), 8.42 (d, J=2.0 Hz, 1H, ArH), 8.19 (dd, J=8.8, 2.0Hz, 1H, ArH), 8.09 (d, J=8.8 Hz, 1H, ArH), 7.83 (d, J=1.2 Hz, 1H, ArH),6.67 (d, J=2.0 Hz, 1H, ArH), 6.41 (bs, OH), 4.56 (d, J=14.0 Hz, 1H,CHH), 4.37 (d, J=14.0 Hz, 1H, CHH), 1.41 (s, 3H, CH₃); ¹⁹F NMR (CDCl₃,decoupling) δ-60.44, −61.25; HRMS (ESI) m/z calcd for C₁₆H₁₂F₆N₄O₂:407.0943 [M+H]⁺; Found: 407.0943 [M+H]⁺; mp 153-155° C.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₂₁H₁₆F₄N₄O₂) (1015)

To a solution of 3-(4-fluorophenyl)-pyrazole (0.30 g, 0.00185 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.22g, 0.00555 mol). After addition, the resulting mixture was stirred for 3h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8) (0.65 g, 0.00185 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (2:1) as eluent to afford 0.32 g(40%) of the titled compound as pinkish solid.

Compound 1015 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.30 (s, 1H, NH), 8.41 (d, J=2.0 Hz, 1H, ArH), 8.21 (dd, J=8.2 Hz,J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.2 Hz, 1H, ArH), 7.68 (d, J=2.0 Hz, 1H,ArH), 7.64-7.59 (m, 2H, ArH), 7.11-7.05 (m, 2H, ArH), 6.65 (d, J=3.0 Hz,1H, ArH), 6.31 (s, 1H, OH), 4.50 (d, J=13.6 Hz, 1H, CH), 4.30 (d, J=13.6Hz, 1H, CH), 1.42 (s, 3H, CH₃); Mass (ESI, Positive): 433.1312 [M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-morpholinopropanamide(C₁₆H₁₈F₃N₃O₃) (1016)

Under an argon atmosphere, 1.0 mL of lithium bis(trimethylsilyl)amide inTHF (1 mmol, Aldrich, 1 M solution in THF) was slowly added to asolution of 0.09 mL of morpholine (0.67 mmol) in THF (10 mL) at −78° C.and stirred for 30 min at that temperature. A solution of 8 (234 mg,0.67 mmol) in 5 mL of THF was added dropwise to the solution. Thereaction mixture was stirred at the same temperature for 30 min, thenstirred overnight at RT, and quenched by an addition of sat. NH₄Clsolution. The mixture was concentrated under reduced pressure, dispersedinto excess EtOAc, dried over Na₂SO₄, concentrated and purified by flashcolumn chromatography (EtOAc/hexane) to give the target compound (209mg, yield 88%) as white solid.

Compound 1016 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.36 (bs, 1H, NH), 8.08 (d, J=1.6 Hz, 1H), 7.94 (dd, J=8.4, 1.6 Hz, 1H),7.80 (d, J=8.4 Hz, 1H), 3.68 (m, 4H), 3.28 (d, J=13.2 Hz, 1H), 2.55 (m,4H), 2.42 (d, J=13.2 Hz, 1H), 1.50 (bs, 1H, OH), 1.42 (s, 3H); ¹⁹F NMR(acetone-d₆, 400 MHz) δ-62.20; LCMS (ESI) m/z calcd for C₁₆H₁₉F₃N₃O₃:358.1379.

Found: 358.1383 [M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide(C₁₆H₁₂F₆N₄O₂) (1017)

To a solution of 4-trifluoromethyl-pyrazole (0.20 g, 0.00147 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.18g, 0.004409 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8) (0.516 g, 0.00147 mol) was added to above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (19:1) as eluent to afford0.30 g (50%) of the titled compound as white foam.

Compound 1017 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.38 (s, 1H, NH), 8.45 (d, J=2.0 Hz, 1H, ArH), 8.25-8.22 (m, 2H, ArH &Pyrazole-H), 8.11 (d, J=8.2 Hz, 1H, ArH), 7.82 (s, 1H, Pyrazole-H), 6.39(s, 1H, OH), 4.55 (d, J=14.0 Hz, 1H, CH), 4.37 (d, J=14.0 Hz, 1H, CH),1.40 (s, 3H, CH₃); Mass (ESI, Positive): 407.0945 [M+H]⁺.

Triazoles 1018 and 1019:(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(1H-1,2,4-triazol-1-yl)propanamide(C₁₄H₁₂F₃N₅O₂) (1018)

To a dry, nitrogen-purged 50 mL round-bottom flask, epoxide (10, 270 mg,1 mmol), 1,2,4-triazole (69 mg, 1 mmol) and K₂CO₃ (268 mg, 2 mmol) weredispersed into 10 mL of 2-butanone (methylethylketone (MEK)). Themixture was heated to reflux for 12 h. The resulting mixture was cooleddown to RT. The volume of mixture was reduced under reduced pressure,poured into water, and extracted with ethyl acetate (3 times). Theorganic layer was dried over MgSO₄, concentrated and purified by flashcolumn chromatography (ethyl acetate/hexane 2:3 v/v) on silica gel toproduce target product (143 mg, 43% yield). Compound 1018 wascharacterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ 9.10 (bs, 1H, NH),8.15 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.78(d, J=8.4 Hz, 1H), 5.70 (bs, 1H, OH), 4.79 (d, J=14.0 Hz, 1H), 4.35 (d,J=14.0 Hz, 1H), 1.53 (s, 3H); ¹⁹F NMR (CDCl₃, 400 MHz) δ-62.22; HRMS(ESI) m/z calcd for C₁₄H₁₂F₃N₅O₂ Exact Mass: 340.1021 [M+H]⁺. Found:340.1067 [M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)propanamide(C₁₅H₁₁F₆N₅O₂) (1019)

To a dry, nitrogen-purged 50 mL round-bottom flask, epoxide (10, 270 mg,1 mmol), 3-(trifluoromethyl)-1H-1,2,4-triazole (137 mg, 1 mmol) andK₂CO₃ (268 mg, 2 mmol) were dispersed into 10 mL of 2-butanone(methylethylketone or MEK). The mixture was heated to reflux for 12 h.The resulting mixture was cooled down to RT. The volume of mixture wasreduced under reduced pressure, poured into water, and extracted withethyl acetate (3 times). The organic layer was dried over MgSO₄,concentrated and purified by flash column chromatography (ethylacetate/hexane 2:3 v/v) on silica gel to produce target product (213 mg,53% yield).

Compound 1019 was characterized as follows: ¹H NMR (acetone-d₆, 400 MHz)δ 9.88 (bs, 1H, NH), 9.44 (s, 1H), 8.44 (s, 1H), 8.25 (d, J=8.4 Hz, 1H),8.04 (d, J=8.4 Hz, 1H), 4.82 (d, J=14.4 Hz, 1H), 4.61 (d, J=14.4 Hz,1H), 2.88 (bs, 1H, OH), 1.61 (s, 3H); ¹⁹F NMR (CDCl₃, 400 MHz) δ-62.26,−65.25; HRMS (ESI) m/z calcd for C₁₅H₁₁F₆N₅O₂ Exact Mass: 408.0895[M+H]⁺.

Found: 408.0898 [M+H]⁺.

(R)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂F₄N₄O₂) (1020)

To a solution of 4-fluoro-1H-pyrazole (0.1 g, 1.16 mmol) in anhydrousTHF (10 mL), which was cooled in an ice bath under an argon atmosphere,was added sodium hydride (60% dispersion in mineral oil, 0.12 g, 2.91mmol). After addition, the resulting mixture was stirred for 3 h.(S)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(S-isomer of 8 (8S)*; 0.41 g, 1.16 mmol) was added to the abovesolution, and the resulting reaction mixture was allowed to stirovernight at RT under argon atmosphere. The reaction was quenched bywater and extracted with ethyl acetate. The organic layer was washedwith brine, dried with anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The mixture was purified by flash columnchromatography using ethyl acetate and hexanes (⅔, v/v) as eluent toafford the titled compound (127 mg, 71%) as white solid.

Compound 1020 was characterized as follows: ¹H NMR (400 MHz, CDCl₃) δ9.07 (bs, 1H, NH), 8.01 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.4, 2.0 Hz, 1H),7.78 (d, J=8.4 Hz, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.34 (d, J=4.4 Hz, 1H),5.92 (s, OH), 4.54 (d, J=14.0 Hz, 1H), 4.16 (d, J=14.4 Hz, 1H), 1.47 (s,3H); ¹⁹F NMR (CDCl₃, decoupling) δ-62.23, −176.47; HRMS (ESI) m/z calcdfor C₁₅H₁₂F₄N₄O₂: 357.0975 [M+H]⁺; Found: 357.0984 [M+H]⁺; [α]_(D)²⁴+126.7° (c=1.0, MeOH) (compared with S-isomer: [α] D²⁴−136.0° (c=0.5,MeOH)).

*: 8S was synthesized from L-proline using the same procedure as for 8(i.e., the R-isomer), as outlined in Scheme 1.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-1H-pyrrol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₆H₁₃F₄N₃O₂) (1021)

To a solution of 3-fluoro-1-(triisopropylsilyl)-1H-pyrrole (1.21 g, 5mmol) in 20 mL of anhydrous THF, n-tetrabutylammonium fluoridetrihydrate in tetrahydrofuran (7.5 mL, 7.5 mmol; 1M) was added at RTunder argon atmosphere. The solution was stirred for 1 h. Withoutwork-up procedure, the flask was cooled down to 0° C. at ice-water bath.To the solution, NaH of 60% in mineral oil (133 mg, 3.33 mmol) wasadded. The reaction mixture was stirred for 30 min and epoxide 10 (450mg, 1.67 mmol) in anhydrous THF was added through dropping funnel underargon atmosphere at the ice-water bath and stirred overnight at RT.After quenching with 1 mL of H₂O, the reaction was condensed underreduced pressure, and then dispersed into 50 mL of EtOAc, washed withwater, evaporated, dried over anhydrous MgSO₄, and evaporated todryness. The mixture was purified with flash column chromatography byEtOAc/hexane=1/1 as eluent, and then the condensed compounds wererecrystallized with EtOAc/hexane to give a target product 1021 (181 mg,31%) as white solid.

Compound 1021 was characterized as follows: ¹H NMR (400 MHz, CDCl₃) δ8.91 (bs, 1H, NH), 8.03 (d, J=2.0 Hz, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H),7.81 (d, J=8.4 Hz, 1H), 6.47 (m, 1H), 6.41 (m, 1H), 5.91 (dd, J=2.8, 2.0Hz, 1H), 4.36 (d, J=14.4 Hz, 1H), 3.98 (d, J=14.4 Hz, 1H), 1.54 (s, 3H);¹⁹F NMR (CDCl₃, decoupling) δ-62.18, −164.26; HRMS (ESI) m/z calcd forC₁₆H₁₄F₄N₃O₂: 356.1022 [M+H]⁺, Found: 356.1021 [M+H]⁺; 378.0839 [H+Na]⁺.

(S)—N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₄H₁₁F₄N₅O₂) (1022)

(R)-3-Bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide

(R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4, 1.03 g, 0.005625 mol)reacted with thionyl chloride (0.80 g, 0.006751 mol), trimethylamine(0.74 g, 0.007313 mol), and 5-amino-3-(trifluoromethyl)picolinonitrile(1.00 g, 0.005344 mol) to afford the titled compound. The product waspurified by a silica gel column using hexanes and ethyl acetate (2:1) aseluent to afford 1.70 g (90%) of the titled compound as a yellowishsolid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H, NH), 9.41 (d, J=2.0 Hz, 1H,ArH), 8.90 (d, J=2.0 Hz, 1H, ArH), 6.51 (s, 1H, OH), 3.84 (d, J=10.4 Hz,1H, CH), 3.61 (d, J=10.4 Hz, 1H, CH), 1.50 (s, 3H, CH₃); Mass (ESI,Positive): 351.9915 [M+H]⁺.

(S)—N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide

To a solution of 4-fluoro-pyrazole (0.20 g, 0.0023237 mol) in anhydrousTHF (5 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.28 g,0.0069711 mol). After addition, the resulting mixture was stirred for 3h.(R)-3-Bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide(0.82 g, 0.0023237 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using hexanes and ethyl acetate (1:1) as eluent to afford 0.50 g(60.2%) of the titled compound as white solid.

Compound 1022 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.64 (s, 1H, NH), 9.32 (d, J=2.0 Hz, 1H, ArH), 8.82 (d, J=2.0 Hz, 1H,ArH), 7.75 (d, J=4.8 Hz, 1H, Pyrazole-H), 7.40 (d, J=4.0 Hz, 1H,Pyrazole-H), 6.41 (s, 1H, OH), 4.39 (d, J=14.0 Hz, 1H, CH), 4.22 (d,J=14.0 Hz, 1H, CH), 1.36 (s, 3H, CH₃); (ESI, Positive): 358.0939 [M+H]⁺,380.0749 [M+Na]⁺.

(S)-5-(3-(4-Fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamido)picolinamide(C₁₃H₁₄FN₅O₃) (1023)

(R)-3-Bromo-N-(6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropanamide

(R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4, 3.24 g, 0.017674 mol)reacted with thionyl chloride (2.53 g, 0.021208 mol), trimethylamine(2.33 g, 0.022976 mol), and 5-aminopicolinonitrile (2.00 g, 0.01679 mol)to afford the titled compound. The product was purified by a silica gelcolumn using dichloromethane (DCM) and methanol (19:1) as eluent toafford 4.40 g (92%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H, NH), 9.12 (d, J=2.4 Hz, 1H,ArH), 8.44 (dd, J=8.8 Hz, J=2.4 Hz, 1H, ArH), 8.00 (d, J=8.8 Hz, 1H,ArH), 6.40 (s, 1H, OH), 3.83 (d, J=10.4 Hz, 1H, CH), 3.59 (d, J=10.4 Hz,1H, CH), 1.49 (s, 3H, CH₃); Mass (ESI, Positive): 284.0042 [M+H]⁺.

(S)-5-(3-(4-Fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamido)picolinamide

To a solution of 4-fluoro-pyrazole (0.20 g, 0.0023237 mol) in anhydrousTHF (5 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.28 g,0.0069711 mol). After addition, the resulting mixture was stirred for 3h. (R)-3-Bromo-N-(6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropanamide(0.66 g, 0.0023237 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using DCM and methanol (9:1) as eluent to afford 0.10 g (15%) ofthe titled compound as white solid.

Compound 1023 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.08 (s, 1H, NH), 8.89 (d, J=2.4 Hz, 1H, ArH), 8.30 (dd, J=8.2 Hz,J=2.4 Hz, 1H, ArH), 8.01 (s, 1H, NH), 7.98 (d, J=8.2 Hz, 1H, ArH), 7.73(d, J=4.4 Hz, 1H, Pyrazole-H), 7.51 (s, 1H, NH), 7.42 (d, J=4.0 Hz, 1H,Pyrazole-H), 6.24 (s, 1H, OH), 4.38 (d, J=14.0 Hz, 1H, CH), 4.42 (d,J=14.0 Hz, 1H, CH), 1.34 (s, 3H, CH₃); Mass (ESI, Positive): 308.1177[M+H]⁺, 330.0987 [M+Na]⁺.

N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-methylpropanamide(C₁₅H₁₂F₄N₄O) (1024)

3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide

3-Bromo-2-methylpropanoic acid (2.00 g, 0.011976 mol) reacted withthionyl chloride (1.71 g, 0.014371 mol), trimethylamine (1.58 g,0.015569 mol), and 4-amino-2-(trifluoromethyl)benzonitrile (2.12 g,0.011377 mol) to afford the titled compound. The product was purified bya silica gel column using hexanes and ethyl acetate (2:1) as eluent toafford 3.50 g (91%) of the titled compound as a yellow to light brownsolid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H, NH), 8.30 (s, 1H, ArH), 8.12(d, J=8.2 Hz, 1H, ArH), 8.03 (d, J=8.2 Hz, 1H, ArH), 3.72-3.67 (m, 1H,CH), 3.63-3.59 (m, 1H, CH), 3.03-2.97 (m, 1H, CH), 1.24 (d, J=6.8 Hz,3H, CH₃); Mass (ESI, Negative): 334.85[M−H]⁻.

N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-methylpropanamide

To a solution of 4-fluoro-pyrazole (0.20 g, 0.0023237 mol) in anhydrousTHF (5 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.28 g,0.0069711 mol). After addition, the resulting mixture was stirred for 3h. 3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide(0.78 g, 0.0023237 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using hexanes and ethyl acetate (1:1) as eluent to afford 0.050 gof the titled compound as yellowish solid.

Compound 1024 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.77 (s, 1H, NH), 8.25 (s, 1H, ArH), 8.10 (d, J=8.2 Hz, 1H, ArH), 7.96(d, J=8.2 Hz, 1H, ArH), 7.85 (d, J=4.4 Hz, 1H, Pyrazole-H), 7.47 (d,J=4.4 Hz, 1H, Pyrazole-H), 4.35-4.30 (m, 1H, CH), 4.12-4.07 (m, 1H, CH),3.12-3.10 (m, 1H, CH), 1.22 (d, J=6.8 Hz, 3H, CH₃).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₂₁H₁₆F₄N₄O₂) (1025)

To a solution of 4-(4-fluorophenyl)-1H-pyrazole (0.20 g, 0.0012334 mol)in anhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.15g, 0.0037001 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.43 g, 0.0012334 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (19:1) as eluent to afford0.33 g (62%) of the titled compound as white solid.

Compound 1025 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.29 (s, 1H, NH), 8.41 (s, 1H, ArH), 8.21 (d, J=8.8 Hz, 1H, ArH), 8.05(d, J=8.8 Hz, 1H, ArH), 7.68 (s, 1H, Pyrazole-H), 7.61 (t, J=6.4 Hz, 2H,ArH), 7.08 (t, J=8.4 Hz, 2H, ArH), 6.65 (s, 1H, Pyrazole-H), 6.30 (s,1H, OH), 4.51 (d, J=14.0 Hz, 1H, CH), 4.31 (d, J=14.0 Hz, 1H, CH), 1.42(s, 3H, CH₃); Mass (ESI, Negative): 431.12 [M−H]⁻.

(S)-3-((1H-1,2,4-Triazol-3-yl)amino)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₄H₁₃F₃N₆O₂) (1026)

Under argon atmosphere, 100 mL round bottom flask was cooled down to 0°C. at ice-water bath. NaH of 60% in mineral oil (265 mg, 6.6 mmol) wasadded to the flask at the ice-water bath and anhydrous THF (20 mL) waspoured into the flask at that temperature. Into the flask,3-amino-1,2,4-triazole (164 mg, 2 mmol) was added into the flask at thattemperature and the reaction mixture was stirred for 30 min. Then, aprepared solution of(R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 702 mg, 2 mmol) in anhydrous THF (10 mL) was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at RT. After quenching with 1 mL of H₂O, the reaction mixturewas condensed under reduced pressure, and then dispersed into 50 mL ofEtOAc, washed with water, evaporated, dried over anhydrous MgSO₄, andevaporated to dryness. The mixture was purified with flash columnchromatography with an eluent of EtOAc/hexane (2:1 v/v) to give a targetproduct as brown solid.

Compound 1026 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.10 (bs, 1H, C(O)NH), 8.01 (m, 1H, ArH), 7.87 and 7.81 (dd, J=8.4, 2.0Hz, 1H, ArH), 7.78 (d, J=8.4 Hz, 1H, ArH), 7.72 and 7.51 (s, 1H, ArH),5.90 and 5.65 (bs, 1H, NH), 4.74 (bs, 1H, NH), 4.56 and 4.55 (d, J=14.4and 13.6 Hz, 1H, CH₂), 4.24 (bs, 1H, OH), 4.07 and 3.97 (d, J=13.6 and14.4 Hz, 1H, CH₂), 1.56 and 1.48 (s, 3H, CH₃); ¹⁹F NMR (acetone-d₆, 400MHz) δ-62.24; MS (ESI) m/z 353.03 [M−H]⁻; 355.10 [M+H]⁺; HRMS (ESI) m/zcalcd for C₁₄H₁₃F₃N₆O₂: 355.1130 [M+H]⁺, Found: 355.1128 [M+H]⁺.

tert-Butyl(S)-(1-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-pyrazol-4-yl)carbamate(C₂₀H₂₂F₃N₅O₄) (1027)

tert-Butyl-1H-pyrazol-4-ylcarbamate (1027a)

Under argon atmosphere, to a solution of 1H-pyrazol-4-amine (2 g, 28.9mmol) and di-tert-butyl dicarbonate (6.3 g, 28.9 mmol) in 100 mL ofanhydrous THF was added triethylamine (1.68 mL, 12 mmol) at 0° C. Afterstirring for 30 min, the temperature was raised to RT and the mixturewas stirred for 2 h. The reaction mixture was condensed under reducedpressure, and then dispersed into 50 mL of EtOAc, washed with water,evaporated, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography with an eluent ofEtOAc/hexane in a 1:1 v/v ratio, and then the condensed compounds werethen recrystallized using EtOAc/hexane (1:1 v/v) to give a targetproduct. ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (s, 2H, ArH), 6.29 (bs, 1H, NH),1.51 (s, 9H, C(CH₃)₃); MS (ESI) m/z 182.1 [M−H]⁻.

(S)-tert-Butyl(1-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-pyrazol-4-yl)carbamate

Under argon atmosphere, a 100 mL round bottom flask was cooled down to0° C. at ice-water bath. NaH of 60% in mineral oil (160 mg, 4 mmol) wasadded to the flask at the ice-water bath and anhydrous THF (20 mL) waspoured into the flask at that temperature. Into the flask,tert-butyl-1H-pyrazol-4-ylcarbamate (1027a, 366 mg, 2 mmol) was added atthat temperature and the reaction mixture was stirred for 30 min, then aprepared solution of(R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 702 mg, 2 mmol) in anhydrous THF was added through a dropping funnelunder argon atmosphere at the ice-water bath and stirred overnight atRT. After quenching with 1 mL of H₂O, the reaction was condensed underreduced pressure, and then dispersed into 50 mL of EtOAc, washed withwater, evaporated, dried over anhydrous MgSO₄, and evaporated todryness. The mixture was purified with flash column chromatography usingEtOAc/hexane (2:1 v/v) as an eluent to give a target product (563 mg,62%) as yellowish solid.

Compound 1027 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.13 (bs, 1H, C(O)NH), 8.01 (d, 1H, J=8.4 Hz, ArH), 7.85 (dd, J=8.4, 1.6Hz, 1H, ArH), 7.76 (d, J=8.4 Hz, 1H, ArH), 7.63 (s, 1H, ArH), 7.43 (s,1H, ArH), 6.21 (bs, 1H, C(O)NH), 6.17 (bs, 1H, OH), 4.54 (d, J=14.0 Hz,1H, CH₂), 4.17 (d, J=14.0 Hz, 1H, CH₂), 1.47 (s, 9H, C(CH₃)₃), 1.45 (s,3H, CH₃); ¹⁹F NMR (acetone-d₆, 400 MHz) δ-62.10; MS (ESI) m/z 452.11[M−H]⁻; 454.06 [M+H]⁺.

(S)-3-(4-Amino-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₄F₃N₅O₂) (1028)

Under argon atmosphere, a 100 mL round bottom flask was cooled down to0° C. at ice-water bath. 5 mL of acetyl chloride was added dropwise tothe solution of 1027 (815 mg, 1.80 mmol) of anhydrous EtOH (20 mL) atthe ice-water bath. The reaction mixture was stirred for 30 min at thattemperature. The solvent was concentrated under reduced pressure, andthen dispersed into 50 mL of EtOAc, washed with water, evaporated, driedover anhydrous MgSO₄, and evaporated to dryness. The mixture waspurified with flash column chromatography EtOAc/hexane (using 3:1 to 6:1v/v ratios) as an eluent to give the target product (583 mg, 92%) asbrown solid.

Compound 1028 was characterized as follows: ¹H NMR (acetone-d₆, 400 MHz)δ 10.07 (bs, 1H, C(O)NH), 8.50 (s, 1H, ArH), 8.46 (s, 1H, ArH), 8.26 (d,J=8.0 Hz, 1H, ArH), 8.01 (d, J=8.0 Hz, 1H, ArH), 7.83 (s, 1H, ArH), 4.73(d, J=14.0 Hz, 1H, CH₂), 4.53 (d, J=14.0 Hz, 1H, CH₂), 2.95 (bs, 1H,OH), 1.51 (s, 3H, CH₃); ¹⁹F NMR (acetone-d₆, 400 MHz) δ 114.77; MS (ESI)m/z 351.98 [M−H]⁻; 354.08 [M+H]⁺.

N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)propanamide(C₁₄H₁₀F₄N₄O) (1029)

3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)propanamide (C₁₁H₈BrF₃N₂O)

3-Bromopropanoic acid (2.00 g, 0.0130745 mol) reacted with thionylchloride (1.87 g, 0.0156894 mol), trimethylamine (1.72 g, 0.0169968mol), and 4-amino-2-(trifluoromethyl)benzonitrile (2.31 g, 0.0124207mol) to afford the titled compound. The product was purified by a silicagel column using DCM and methanol (19:1) as eluent to afford 2.31 g(55%) of the titled compound as yellowish solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.85 (s, 1H, NH), 8.28 (d, J=2.4 Hz, 1H, ArH), 8.12 (dd,J=8.8 Hz, J=2.4 Hz, 1H, ArH), 7.99 (d, J=8.8 Hz, 1H, ArH), 3.76 (t,J=6.0 Hz, 2H, CH₂), 3.06 (t, J=6.0 Hz, 2H, CH₂).

N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)propanamide(C₁₄H₁₀F₄N₄O)

To a solution of 4-fluoro-pyrazole (0.20 g, 0.0023237 mol) in anhydrousTHF (5 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.28 g,0.0069711 mol). After addition, the resulting mixture was stirred for 3h. 3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)propanamide (1029a, 0.75g, 0.0023237 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at RT under argon. Thereaction was quenched by water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using DCM and methanol (19:1) as eluent to afford 0.75 mg (10%)of the titled compound as white solid.

Compound 1029 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.81 (s, 1H, NH), 8.25 (d, J=2.4 Hz, 1H, ArH), 8.10 (dd, J=8.8 Hz,J=2.4 Hz, 1H, ArH), 7.95 (d, J=8.8 Hz, 1H, ArH), 7.88 (s, 1H,Pyrazole-H), 7.46 (s, 1H, Pyrazole-H), 4.35 (t, J=6.0 Hz, 2H, CH₂), 2.79(t, J=6.0 Hz, 2H, CH₂); Mass (ESI, Negative): 325.03 [M−H]⁻.

(S)-tert-Butyl(1-(3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-pyrazol-4-yl)carbamate(C₁₉H₂₁F₃N₆O₄) (1030)

Under argon atmosphere, a 50 mL round bottom flask was cooled down to 0°C. at an ice-water bath. NaH of 60% in mineral oil (160 mg, 4 mmol) wasadded to the flask at the ice-water bath and anhydrous THF (10 mL) waspoured into the flask at that temperature.Tert-butyl-1H-pyrazol-4-ylcarbamate (1027a, 183 mg, 1 mmol) was addedinto the flask at that temperature and the reaction mixture was stirredfor 30 min. Then a prepared solution of(R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide(352 mg, 1 mmol) in anhydrous THF was added through dropping funnelunder argon atmosphere at the ice-water bath and stirred overnight atRT. After quenching with 1 mL of H₂O, the reaction was condensed underreduced pressure, and then dispersed into 30 mL of EtOAc, washed withwater, evaporated, dried over anhydrous MgSO₄, and evaporated todryness. The mixture was purified with flash column chromatography as aneluent EtOAc/hexane to give the target product (273 mg, 60%) asyellowish solid.

Compound 1030 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.28 (bs, 1H, C(O)NH), 8.80 (s, 1H, ArH), 8.67 (s, 1H, ArH), 7.63 (bs,1H, C(O)NH), 7.43 (s, 1H, ArH), 6.29 (bs, 1H, OH), 6.21 (s, 1H, ArH),4.55 (d, J=14.0 Hz, 1H, CH₂), 4.18 (d, J=14.0 Hz, 1H, CH₂), 1.51 (s, 3H,CH₃) 1.47 (s, 9H, C(CH₃)₃); ¹⁹F NMR (CDCl₃, 400 MHz) δ-62.11; MS (ESI)m/z 453.16 [M−H]⁻; 477.16 [M+Na]⁺.

(S)-3-(4-Acetamido-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₇H₁₆F₃N₅O₃) (1031)

Under argon atmosphere, to a solution of 1028 (150 mg, 0.43 mmol) andtriethyl amine (0.09 mL, 0.64 mmol) in 10 mL of anhydrous DCM was addedacetyl chloride (AcCl, 0.038 mL, 0.53 mmol) at an ice-water bath. Afterstirring for 30 min, the temperature was raised to RT and the mixturewas stirred for 2 h. The reaction mixture was condensed under reducedpressure, and then dispersed into 10 mL of EtOAc, washed with water,evaporated, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography as an eluentacetone/hexane (½, v/v) to produce 1031 (150 mg, 89%) as white solids.

Compound 1031 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.08 (bs, 1H, C(O)NH), 7.92 (bs, 1H, C(O)NH), 7.82-7.80 (m, 2H, ArH),7.69 (d, J=8.4 Hz, 1H, ArH), 7.44 (s, 1H, ArH), 7.15 (s, 1H, ArH), 6.10(bs, 1H, OH), 4.49 (d, J=13.6 Hz, 1H, CH₂), 4.13 (d, J=13.6 Hz, 1H,CH₂), 2.04 (s, 3H, NH(CO)CH₃), 1.39 (s, 3H, CH₃); ¹⁹F NMR (CDCl₃, 400MHz) δ −62.20; MS (ESI) m/z 394.06 [M−H]⁻; 396.11 [M+H]⁺.

(S)-3-(4-Amino-1H-pyrazol-1-yl)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl2-chloroacetate (C₁₇H₁₅ClF₃N₅O₃) (1032); and(S)-3-(4-(2-Chloroacetamido)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₇H₁₅ClF₃N₅O₃) (1033)

Under argon atmosphere, to a solution of 1028 (263 mg, 0.75 mmol) andtriethyl amine (0.16 mL, 1.12 mmol) in 50 mL of anhydrous DCM was addedchloroacetyl chloride (0.074 mL, 0.94 mmol) at an ice-water bath. Afterstirring for 30 min, the temperature was raised to RT and the mixturewas stirred for 2 h. The reaction mixture was condensed under reducedpressure, and then dispersed into 30 mL of EtOAc, washed with water,evaporated, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography as an eluentEtOAc/hexane (3/1, v/v) to produce 1032 (105 mg, 33%) and 1033 (117 mg,36%) as yellowish solids. Total yield 70%.

Compound 1032 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.22 (bs, NH₂), 8.10 (bs, 1H, C(O)NH), 7.93 (d, J=1.8 Hz, 1H, ArH), 7.86(d, J=1.8 Hz, 1H, ArH), 7.79 (d, J=8.4 Hz, 1H, ArH), 5.16 (d, J=14.8 Hz,1H, CH₂), 4.62 (d, J=14.8 Hz, 1H, CH₂), 4.11 (s, 2H, CH₂Cl), 1.77 (s,3H, CH₃); ¹⁹F NMR (CDCl₃, 400 MHz) δ 114.77; MS (ESI) m/z 428.03 [M−H]⁻;452.02 [M+Na]⁺.

Compound 1033 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.12 (bs, 1H, C(O)NH), 8.12 (bs, 1H, C(O)NH), 7.99 (d, J=1.6 Hz, 1H,ArH), 7.92 (s, 1H, ArH), 7.87 (dd, J=8.8, 1.6 Hz, 1H, ArH), 7.76 (d,J=8.8 Hz, 1H, ArH), 7.61 (s, 1H, ArH), 6.11 (bs, 1H, OH), 4.60 (d,J=13.6 Hz, 1H, CH₂), 4.22 (d, J=13.6 Hz, 1H, CH₂), 4.17 (s, 2H, CH₂Cl),1.47 (s, 3H, CH₃); ¹⁹F NMR (CDCl₃, 400 MHz) δ-62.19; MS (ESI) m/z 428.00[M−H]⁻; 452.01 [M+Na]⁺.

(S)-Methyl(1-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-pyrazol-4-yl)carbamate(C₁₇H₁₆F₃N₅O₄) (1034)

Under argon atmosphere, to a solution of 1028 (170 mg, 0.48 mmol) andtriethyl amine (0.16 mL, 1.15 mmol) in 10 mL of anhydrous DCM was addedmethyl carbonochloridate (0.04 mL, 0.58 mmol) at ice-water bath. Afterstirring for 30 min, the temperature was raised to RT and the mixturestirred for 2 h. The reaction mixture was condensed under reducedpressure, and then dispersed into 10 mL of EtOAc, washed with water,evaporated, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography as an eluentEtOAc/hexane (2/1, v/v) to produce 1034 (141 mg, 71%) as white solids.

Compound 1034 was characterized as follows: ¹H NMR (CDCl₃, 400 MHz) δ9.07 (bs, 1H, C(O)NH), 7.91 (s, 1H, ArH), 7.79 (d, J=7.2 Hz, 1H, ArH),7.69 (d, J=7.2 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.40 (s, 1H, ArH), 6.33(bs, 1H, NH), 6.08 (bs, 1H, OH), 4.50 (d, J=13.6 Hz, 1H, CH₂), 4.12 (d,J=13.6 Hz, 1H, CH₂), 3.67 (s, 3H, NH(CO)OCH₃), 1.39 (s, 3H, CH₃); ¹⁹FNMR (CDCl₃, 400 MHz) δ-62.21; MS (ESI) m/z 410.30 [M−H]⁻; 413.21 [M+H]⁺.

(S)-3-(4-Acetyl-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₇H₁₅F₃N₄O₃) (1035)

To a solution of 1-(1H-pyrazol-4-yl)ethanone (0.10 g, 0.000908 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.11g, 0.002725 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 0.32 g, 0.000908 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (19:1) as eluent to afford70 mg (20%) of the titled compound as yellowish solid.

Compound 1035 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.37 (s, 1H, NH), 8.45 (d, J=1.2 Hz, 1H, ArH), 8.25 (s, 1H,Pyrazole-H), 8.23 (d, J=8.2 Hz, J=1.2 Hz, 1H, ArH), 8.10 (d, J=8.2 Hz,1H, ArH), 7.86 (s, 1H, Pyrazole-H), 6.37 (s, 1H, OH), 4.50 (d, J=14.0Hz, 1H, CH), 4.33 (d, J=14.0 Hz, 1H, CH), 2.34 (s, 3H, CH₃), 1.39 (s,3H, CH₃); mass (ESI, Negative): 379.14 [M−H]⁻; (ESI, Positive): 413.18[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-nitro-1H-pyrazol-1-yl)propanamide(C₁₅H₁₂F₃N₅O₄) (1036)

To a solution of 4-nitro-1H-pyrazole (0.10 g, 0.0008844 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.106g, 0.002653 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 0.31 g, 0.0008844 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexanes and ethyl acetate (1:1) as eluent toafford 0.15 g (44%) of the titled compound as off-white solid.

Compound 1036 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.36 (s, 1H, NH), 8.69 (s, 1H, Pyrazole-H), 8.45 (d, J=1.2 Hz, 1H,ArH), 8.23 (d, J=8.8 Hz, J=1.2 Hz, 1H, ArH), 8.19 (s, 1H, Pyrazole-H),8.11 (d, J=8.8 Hz, 1H, ArH), 6.47 (s, 1H, OH), 4.56 (d, J=14.0 Hz, 1H,CH), 4.38 (d, J=14.0 Hz, 1H, CH), 1.41 (s, 3H, CH₃); mass (ESI,Negative): 382.13 [M−H]⁻.

(R)-3-Bromo-N-(6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropanamide(C₁₀H₁₀BrN₃O₂) (1037)

(R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4, 3.24 g, 0.017674 mol)reacted with thionyl chloride (2.53 g, 0.021208 mol), trimethylamine(2.33 g, 0.022976 mol), and 5-aminopicolinonitrile (2.00 g, 0.01679 mol)to afford the titled compound. The product was purified by a silica gelcolumn using DCM and methanol (19:1) as eluent to afford 4.40 g (92%) ofthe titled compound as yellowish solid.

Compound 1037 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.42 (s, 1H, NH), 9.12 (d, J=2.4 Hz, 1H, ArH), 8.44 (dd, J=8.8 Hz,J=2.4 Hz, 1H, ArH), 8.00 (d, J=8.8 Hz, 1H, ArH), 6.40 (s, 1H, OH), 3.83(d, J=10.4 Hz, 1H, CH), 3.59 (d, J=10.4 Hz, 1H, CH), 1.49 (s, 3H, CH₃);mass (ESI, Positive): 284.0042 [M+H]⁺.

(R)-3-Bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide(C₁₁H₉BrF₃N₃O₂) (1038)

(R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4, 1.03 g, 0.005625 mol)reacted with thionyl chloride (0.80 g, 0.006751 mol), trimethylamine(0.74 g, 0.007313 mol), and 5-amino-3-(trifluoromethyl)picolinonitrile(1.00 g, 0.005344 mol) to afford the titled compound. The product waspurified by a silica gel column using hexanes and ethyl acetate (2:1) aseluent to afford 1.70 g (90%) of the titled compound as yellowish solid.

Compound 1038 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.82 (s, 1H, NH), 9.41 (d, J=2.0 Hz, 1H, ArH), 8.90 (d, J=2.0 Hz, 1H,ArH), 6.51 (s, 1H, OH), 3.84 (d, J=10.4 Hz, 1H, CH), 3.61 (d, J=10.4 Hz,1H, CH), 1.50 (s, 3H, CH₃); mass (ESI, Positive): 351.9915 [M+H]⁺.

(R)-3-Bromo-2-hydroxy-2-methyl-N-(quinazolin-6-yl)propanamide(C₁₂H₁₂BrN₃O₂) (1039)

(R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (2.65 g, 0.014503 mol) wasreacted with thionyl chloride (2.07 g, 0.017404 mol), trimethylamine(1.91 g, 0.018854 mol), and quinazolin-6-amine (2.00 g, 0.013778 mol) toafford the titled compound. The product was purified by a silica gelcolumn using hexanes and ethyl acetate (3:1 to 2:1) as eluent to afford0.71 g of the titled compound as yellowish solid.

Compound 1039 was characterized as follows: Mass (ESI, Positive) 309.98[M+H]⁺.

3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)propanamide (C₁₁H₈BrF₃N₂O)(1040)

3-Bromopropanoic acid (2.00 g, 0.0130745 mol) reacted with thionylchloride (1.87 g, 0.0156894 mol), trimethylamine (1.72 g, 0.0169968mol), and 4-amino-2-(trifluoromethyl)benzonitrile (2.31 g, 0.0124207mol) to afford the titled compound. The product was purified by a silicagel column using DCM and methanol (19:1) as eluent to afford 2.31 g(55%) of the titled compound as yellowish solid.

Compound 1040 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.85 (s, 1H, NH), 8.28 (d, J=2.4 Hz, 1H, ArH), 8.12 (dd, J=8.8 Hz,J=2.4 Hz, 1H, ArH), 7.99 (d, J=8.8 Hz, 1H, ArH), 3.76 (t, J=6.0 Hz, 2H,CH₂), 3.06 (t, J=6.0 Hz, 2H, CH₂).

(S)—N-(2-Chloropyridin-4-yl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₂H₁₂ClFN₄O₂) (1041)

(R)-3-Bromo-N-(2-chloropyridin-4-yl)-2-hydroxy-2-methylpropanamide

Thionyl chloride (11.2 mL, 0.154 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (4, 18.3 g, 0.100 mol) in 100 mL of THF under an argon atmosphere.The resulting mixture stirred for 3 h under the same condition. To thiswas added Et₃N (25.7 mL, 0.185 mol) and then stirred for 20 min underthe same condition. After 20 min, 2-chloropyridin-4-amine (9.89 g, 0.077mol), 100 mL of THF were added and then the mixture was allowed to stirovernight at RT. The solvent was removed under reduced pressure to givea solid, which was treated with 100 mL of H₂O, and extracted with EtOAc(2×50 mL). The combined organic extracts were washed with saturatedNaHCO₃ solution (2×100 mL) and brine (100 mL). The organic layer wasdried over MgSO₄ and concentrated under reduced pressure to give asolid, which was dissolved and purified by column chromatography usingCH₂Cl₂/EtOAc (80:20) to give a solid. This solid recrystallized fromCH₂Cl₂/hexane to give 12.6 g (43%) of(R)-3-bromo-N-(2-chloropyridin-4-yl)-2-hydroxy-2-methylpropanamide as alight-yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.06 (bs, 1H, NH), 8.31(d, J=5.6 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.45 (dd, J=5.6, 0.8 Hz, 1H),4.81 (bs, 1H, OH), 3.97 (d, J=10.6 Hz, 1H), 3.60 (d, J=10.6 Hz, 1H),1.64 (s, 3H); MS (ESI) m/z 295.28 [M+H]⁺.

(S)—N-(2-Chloropyridin-4-yl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₂H₁₂ClFN₄O₂)

To a dry, nitrogen-purged 100 mL round-bottom flask equipped with adropping funnel under argon atmosphere, NaH of 60% dispersion in mineraloil (96 mg, 2.4 mmol) was added in 10 mL of anhydrous THF solvent atice-water bath. 4-Fluoro-1H-pyrazole (103 mg, 1.2 mmol) was added andthe solution stirred 30 min at the ice-water bath. Into the flask, thesolution of(R)-3-bromo-N-(2-chloropyridin-4-yl)-2-hydroxy-2-methylpropanamide (293mg, 1.0 mmol) in 5 mL of anhydrous THF was added through dropping funnelunder argon atmosphere at the ice-water bath and stirred overnight atRT. After adding 1 mL of H₂O, the reaction mixture was condensed underreduced pressure, and then dispersed into 50 mL of EtOAc, washed with 50mL (×2) water, evaporated, dried over anhydrous MgSO₄, and evaporated todryness. The mixture was purified with flash column chromatography usingas an eluent EtOAc/hexane as a 1:2 ratio to produce compounds to producethe titled compound (55%) as a white solid.

Compound 1041 was characterized as follows: ¹H NMR (400 MHz, CDCl₃) δ8.90 (bs, 1H, NH), 8.26 (d, J=5.6 Hz, 1H), 7.63 (s, 1H), 7.75 (d, J=4.2Hz, 1H), 7.33 (d, J=4.2 Hz, 1H), 7.31 (dd, J=5.6, 1.2 Hz, 1H), 5.88 (s,1H, OH), 4.53 (d, J=13.6 Hz, 1H), 4.14 (d, J=13.6 Hz, 1H), 1.45 (s, 3H);¹⁹F NMR (CDCl₃, decoupled) δ-176.47; MS (ESI) m/z 298.98 [M+H]⁺; 296.96[M−H]⁻.

(S)-3-Azido-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₂H₁₀F₃N₅O₂) (1042)

A solution of 8 (351 mg, 1 mmol) in DMF (10 mL) was treated with NaN₃(325 mg, 5 nmol) under argon at 80° C. for 24 h. The reaction mixturewas then, cooled and extracted with CH₂Cl₂ (3×20 mL). The combinedorganic layers were washed with H₂O (3×20 mL) and brine, dried andevaporated to give a crude oil, which was purified by silica gelchromatography (EtOAc/n-hexane=1:2, v/v) to afford the titled compoundas a yellow solid (224 mg, 72%).

Compound 1042 was characterized as follows: ¹H NMR (400 MHz, CDCl₃) δ9.00 (bs, 1H, NH), 8.08 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.4Hz, 1H), 3.92 (d, J=12.4 Hz, 1H), 3.50 (d, J=12.4 Hz, 1H), 2.96 (s, 1H,OH), 1.54 (s, 3H); ¹⁹F NMR (CDCl₃, decoupled) δ-62.21; MS (ESI) m/z314.03 [M+H]⁺; 312.18 [M−H]

(S)—N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propanamide(C₁₅H₁₁F₆N₅O₂) (1043)

To a solution of 4-trifluoromethyl-pyrazole (0.10 g, 0.0007349 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.09g, 0.002025 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide(0.26 g, 0.0007349 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (19:1) as eluent to afford0.18 g (60%) of the titled compound as white solid.

Compound 1043 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.63 (s, 1H, NH), 9.31 (s, 1H, ArH), 8.80 (s, 1H, ArH), 8.32 (s, 1H,Pyrazole-H), 7.81 (s, 1H, Pyrazole-H), 6.48 (s, 1H, OH), 4.55 (d, J=14.0Hz, 1H, CH), 4.37 (d, J=14.0 Hz, 1H, CH), 1.42 (s, 3H, CH₃); mass (ESI,Negative): 406.08 [M−H]⁻; (ESI, Positive): [M+H]⁺, 430.13 [M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-2-methylpropanamide(C₂₀H₁₅F₄N₅O₂) (1044)

A mixture of 1042 (57 mg, 0.18 mmol), 1-ethynyl-4-fluorobenzene (0.015mL, 0.18 mmol), and copper iodide (11 mg, 0.055 mmol) in AcCN/H₂O (1/0.5mL) were loaded into a vessel with a cap. The reaction vessels wereplaced in a reactor block in the microwave reactor. A programmablemicrowave (MW) irradiation cycle of 30 min on (300 W) at 100° C. and 25min off (fan-cooled) was executed twice because starting materials wereshown on TLC after the first cycle (total irradiation time, 60 min). Themixture was transferred to a round bottom flask to be concentrated underreduced pressure and poured into EtOAc, which was washed with water anddried over MgSO₄, concentrated, and purified by silica gelchromatography (EtOAc/hexane=2:1) to afford the titled compound asyellow solid (69.8 mg, 90%).

Compound 1044 was characterized as follows: ¹H NMR (400 MHz, acetone-d₆)δ 9.00 (bs, 1H, NH), 8.44 (s, 1H), 8.30 (s, 1H), 8.25 (d, J=8.4 Hz, 1H),8.02 (d, J=8.4 Hz, 1H), 7.89 (dd, J=8.0, 2.4 Hz, 2H), 7.20 (d, J=8.8 Hz,2H), 5.67 (s, 1H, OH), 4.92 (d, J=14.0 Hz, 1H), 4.72 (d, J=14.0 Hz, 1H),1.60 (s, 3H); ¹⁹F NMR (acetone-d₆, decoupled) δ 114.68, 61.64; MS (ESI)m/z 432.11 [M−H]⁻ 434.08 [M+H]⁺. The structure of 1044 was distinguishedfrom its isomer 1045 (see below) by the 2D NMR techniques of NOESY andCOSY.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-2-methylpropanamide(C₂₀H₁₅F₄N₅O₂) (1045)

To a suspension of copper(I)iodide (11 mg, 0.055 mmoL) in acetonitrile(7 mL)/water (3 mL) was added 1042 (57 mg, 0.182 mmol) at RT and then1-ethynyl-4-fluorobenzene (0.015 mL, 0.182 mmol) was added. Theresulting reaction mixture was stirred at RT for 3 days. The mixture wasevaporated under reduced pressure, poured into water:brine (1:1, v/v)and then extracted with ethyl acetate. The combined organic extractswere then washed with brine, dried over sodium sulfate, filtered andevaporated. Purification was by chromatography (silica, 60% ethylacetate in hexane) to afford a yellow solid (51.3 mg, 65%).

Compound 1045 was characterized as follows: ¹H NMR (400 MHz, CDCl₃) δ9.07 (bs, 1H, NH), 7.82-7.80 (m, 1H), 7.79 (s, 1H), 7.76-7.74 (m, 2H),7.72 (dd, J=8.2, 2.8 Hz, 2H), 7.10 (t, J=8.8 Hz, 2H), 5.15 (bs, 1H, OH),4.96 (d, J=14.0 Hz, 1H), 4.61 (d, J=14.0 Hz, 1H), 1.62 (s, 3H); ¹⁹F NMR(CDCl₃, decoupled) δ-62.24, −112.36; MS (ESI) m/z 432.17 [M−H]⁻434.09[M+H]⁺. The structure of 1045 was distinguished from its isomer 1044(see above) by the 2D NMR techniques of NOESY and COSY. E.g., 1045showed an NOE cross-peak between the methylene proton and the triazoleproton indicating that these protons are within ˜4.5 Å of each other aswould be the case for 1045 but not 1044. This cross-peak was not seenfor 1044.

(S)-3-(4-Fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-propanamide(C₁₄H₁₂F₄N₄O₄) (1046)

To a dry, nitrogen-purged 100 mL round-bottom flask equipped with adropping funnel under argon atmosphere containing 4-fluoro-1H-pyrazole(691 mg, 8.03 mmol), NaH of 60% dispersion in mineral oil (674 mg, 16.9mmol) was added in 60 mL of anhydrous THF solvent at ice-water bath. Themixture was stirred 30 min at the ice-water bath. Into the flask throughdropping funnel, a solution of(R)-3-bromo-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide(2.98 g, 8.03 mmol) in 10 mL of anhydrous THF was added under argonatmosphere at the ice-water bath, and stirred overnight at RT. Afteradding 1 mL of H₂O, the reaction mixture was condensed under reducedpressure, and then dispersed into 50 mL of EtOAc, washed with 50 mL (×2)water, evaporated, dried over anhydrous MgSO₄, and evaporated todryness. The mixture was purified with flash column chromatography usingas an eluent EtOAc/hexane in a 1:2 ratio to produce the titled compound(2.01 g, 67%) as yellow solid.

Compound 1046 was characterized as follows: ¹H NMR (400 MHz, CDCl₃) δ9.14 (bs, 1H, NH), 8.01 (s, 1H), 7.97-7.91 (m, 2H), 7.38 (d, J=3.6 Hz,1H), 7.35 (d, J=4.4 Hz, 1H), 5.95 (s, 1H, OH), 4.56 (d, J=14.0 Hz, 1H),4.17 (d, J=14.0 Hz, 1H), 1.48 (s, 3H); ¹⁹F NMR (CDCl₃, decoupled) δ−60.13, −176.47; MS (ESI) m/z 375.08 [M−H]⁻; 377.22 [M+H]⁺; 399.04[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanamide(C₁₅H₁₂F₃IN₄O₂) (1047)

To a solution of 4-iodo-1H-pyrazole (0.20 g, 0.001031 mol) in anhydrousTHF (5 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.124 g,0.003093 mol). After addition, the resulting mixture was stirred for 3h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 0.36 g, 0.001031 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (19:1) as eluent to afford0.25 g (52%) of the titled compound as off-white solid.

Compound 1047 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.36 (s, 1H, NH), 8.45 (s, 1H, ArH), 8.23 (d, J=8.8 Hz, J=1.2 Hz, 1H,ArH), 8.10 (d, J=8.8 Hz, 1H, ArH), 7.78 (s, 1H, Pyrazole-H), 7.46 (s,1H, Pyrazole-H), 6.31 (s, 1H, OH), 4.48 (d, J=14.0 Hz, 1H, CH), 4.31 (d,J=14.0 Hz, 1H, CH), 1.35 (s, 3H, CH₃); mass (ESI, Negative): 463.18[M−H]⁻; (ESI, Positive): 486.96 [M+Na]⁺.

(S)-3-(4-Cyano-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₆H₁₂F₃N₅O₂) (1048)

To a solution of 1H-pyrazole-4-carbonitrile (0.10 g, 0.001074 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.11g, 0.003223 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 0.377 g, 0.001074 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexane and ethyl acetate (1:1 to 1:2) as eluentto afford 0.18 g (46%) of the titled compound as white solid.

Compound 1048 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.35 (s, 1H, NH), 8.45 (d, J=1.2 Hz, 1H, ArH), 8.43 (s, 1H,Pyrazole-H), 8.22 (d, J=8.8 Hz, J=1.2 Hz, 1H, ArH), 8.10 (d, J=8.8 Hz,1H, ArH), 7.98 (s, 1H, Pyrazole-H), 6.41 (s, 1H, OH), 4.45 (d, J=14.0Hz, 1H, CH), 4.36 (d, J=14.0 Hz, 1H, CH), 1.38 (s, 3H, CH₃); mass (ESI,Negative): 362.11 [M−H]⁻; (ESI, Positive): 386.07 [M+Na]⁺.

(S)-3-(4-Chloro-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂ClF₃N₄O₂) (1049)

To a solution of 4-chloro-1H-pyrazole (0.15 g, 0.001463 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.18g, 0.004389 mol). After addition, the resulting mixture was stirred for3 h.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(8, 0.51 g, 0.001463 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at RT underargon. The reaction was quenched by water, and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using dichloromethane and ethyl acetate (19:1) aseluent to afford 0.30 g (55%) of the titled compound as white solid.

Compound 1049 was characterized as follows: ¹H NMR (400 MHz, DMSO-d₆) δ10.38 (s, 1H, NH), 8.46 (s, 1H, ArH), 8.23 (d, J=8.6 Hz, J=1.2 Hz, 1H,ArH), 8.10 (d, J=8.6 Hz, 1H, ArH), 7.83 (s, 1H, Pyrazole-H), 7.47 (s,1H, Pyrazole-H), 6.34 (s, 1H, OH), 4.45 (d, J=14.0 Hz, 1H, CH), 4.27 (d,J=14.0 Hz, 1H, CH), 1.36 (s, 3H, CH₃); mass (ESI, Negative): 371.68[M−H]⁻.

Example 2 Octanol-Water Partition Coefficient (Log P)

Log P is the log of the octanol-water partition coefficient, commonlyused early in drug discovery efforts as a rough estimate of whether aparticular molecule is likely to cross biological membranes. Log P wascalculated using ChemDraw Ultra version is 12.0.2.1016 (Perkin-Elmer,Waltham, Mass. 02451). Calculated Log P values are reported in Table 1in the column labeled ‘Log P (−0.4 to +5.6)’. Lipinski's rule of five isa set of criteria intended to predict oral bioavailability. One of thesecriteria for oral bioavailability is that the Log P is between thevalues shown in the column heading (−0.4 (relatively hydrophilic) to+5.6 (relatively lipophilic) range), or more generally stated<5. One ofthe goals of SARD design was to improve water solubility. The monocyclictemplates of this invention such as the pyrazoles, pyrroles, etc. weremore water soluble than earlier analogs. For instance, one may comparethe Log P values of SARDs from other templates, e.g., alkyl-amine 17,indoline 100 and indole 11, to the monocyclics of the invention(1001-1064).

TABLE 1 In vitro screening of LBD binding (Ki), AR antagonism (IC50),SARD activity, and metabolic stability SARD Activity (% inh): wtARBinding (K_(i) (left)) Full Length (left) and & Transactivation (IC₅₀S.V. (right) Log P (right)) (nM) Full Length S.V. DMPK (MLM) (−0.4 toK_(i) (nM) % inhibition % inhibition T_(1/2) (min) & CL_(int) Compound #Structure +5.6) M.W. (DHT = 1 nM) IC₅₀ (nM) at 1,10 μM at 10 μM(μL/min/mg) Enobosarm (agonist)

3.44 389.89 20.21 ~20 (EC₅₀) Not applicable Not applicableR-Bicalutamide

2.57 430.37 508.84 248.2 0 0 Enzalutamide

4.56 464.44 3641.29 216.3 0 0 ARN-509

3.47 477.43 1452.29 0 0 17

5.69 478.48 28.4 95 100

4.62 468.27 197.67 530.95 60 41 66.87 10.38 11

3.47 405.35 267.39 85.10 65-83 60-100 12.35 56.14 1001

2.29 362.31 327.97 partial agonist 0 0 23.5 29.5 1002

2.03 356.27 No binding 199.36 100 100 77.96  0.89 1003

3.54 414.38 No binding 1152.78 0 0 48.45 14.31 1004

3.93 413.39 322.11 178.77 (partial agonist) 0%, 40% @ 10 μM) 0  3.96175.2  1005

1.78 417.18 No binding 1019.38 50 70 16.51 41.58 1006

2.3 417.18 905.71 148.94 (partial agonist) 0 0 1007

1.66 322.72 No binding 958.77 0 0 1008

0.71 304.73 No binding 1856.8 0 30 24.61 28.16 1009

1.69 (for free amine) 307.78 (for free amine) No binding No inhibition 00 1010

4.09 431.38 259.29 225.91 100 60 17.93 38.66 1011

3.97 414.38 3660 4770 0 0 1012

2.49 356.27 820.97 219.48 82 73 64.07  1.02 1013

1.87 338.28 7398 1441.58 0 1014

3.21 406.28 512.3 204.59 67 (comparable to 11 in the same exp) 54(comparable to 11 in the same exp) 330  0 1015

4.13 432.37 >10000 1742 72 0 1016

1.34 357.33 1874.68 1018.68 52 80 1017

2.79 406.28 898.23 404.39 80 100 Infinity 0 1018

1.42 339.27 No binding 1091.56 0 0 1019

3.23 407.23 No binding 1012.75 68 100 1020

2.03 356.27 No binding 192 84 1021

2.41 355.39 633.23 partial 0 0 1022

1.11 357.26 No binding 92.17 54 81 1023

−0.93 307.28 No binding No effect 0 Infinity 0 1024

2.86 340.28 No binding 463.9 60 70 Infinity 0 1025

3.7 432.37 612.4 969 60 0 1026

1.19 354.29 — — 0 1027

2.24 453.41 1382.06 1153 20 1028

1.07 353.30 227.48 Agonist 1029

2.29 326.25 No Binding 2124 35 40 1030

1.32 454.40 No binding 6108 — 1031

0.78 395.34 No binding No effect — 1032

1.82 429.78 No binding 900.86 1033

1.3 411.34 No binding No effect 1034

1.3 411.34 827 1035

1.2 380.32 757.7 1036

1.9 383.28 2225 36.22 20 1037

0.7 284.11 4547 350.5 >50 1038

1.6 352.11 2490 1039

1.1 310.15 1750 1040

2.8 321.09 — 1041

0.6 298.70 2470 >75 1042

0.8 313.24 — 1043

1.8 407.27 57.91 10 1044

3.4 433.36 316.7 73 1045

3.7 433.36 250.9 84 1046

2.0 376.24 Partial 1047

3.2 464.19 1048

1.9 363.30 1049

2.4 372.73 1002-oxalic 57.99 acid salt 1002- 83.06 succinic acid salt1002-HBr 77.2 1002-tartaric 259.1 acid salt (similar to 1002 in thisexperiment) 1002-HCl 123.5 1050

2.7 417.18 >10000 427 42 0 1051

3.9 477.02 No effect 1052

3.3 482.17 5450 1053

3.4 434.35 No effect 1054

1.7 368.31 — 0 0 1055

2.3 352.31 1552 8087 1057 (Racemate)

2.03 356.27 1058

3.3 435.17 606.5 132.5 70 80 1059

4.3 450.36 600.58 285.1 70 toxic 1060

1061

1062

2.0 376.24 Partial 1062a

— 188.16 No effect 1063

2.8 434.35 1486 216.9

TABLE 2 MLM HLM T_(1/2) CL_(Int) T_(1/2) CL_(Int) Compd ID Structure(min) (μL/min/mg) (min) (μL/min/mg)  11

14.35 48.30 14.62 47.40 1001

23.5 29.5 1002

77.96 0.89 73.36 0.949 1004

3.96 175.2 2.261 306.5 1012

64.07 1.02

Example 3 Transactivation Assay

Methods:

HEK-293 cells were transfected with the indicated receptors and GRE-LUCand CMV-renilla luc. Cells were treated 24 h after transfection andluciferase assay performed 48 h after transfection. The SARD compoundsdid not inhibit transactivation of receptors other than AR until 10 μM.The experimental method is described below.

Human AR was cloned into a CMV vector backbone and was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC,0.01 μg CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 h after transfection and the luciferase assay performed 48 hafter transfection. Transactivation results were based on measuredluciferase light emissions and reported as relative light unit intensity(RLU). The assay was run in antagonist mode (IC₅₀) using known agonistR1881 at its EC₅₀ concentration of 0.1 nM and increasing concentrationsof SARDs of this invention. Agonist mode data was reportedqualitatively, e.g., partial agonist or an approximate EC₅₀ forenobosarm, for some compounds in Table 1. Antagonist data arerepresented as IC₅₀ (nM) obtained from four parameter logistics curveand are reported in Table 1 in the column labeled ‘IC₅₀’.

Results:

Representative example graphs are shown in FIGS. 1A (1002), 2A (11 vs.1002), 3A (1003), 4A (1004), 5A (1005), 6A (1006), 8-12 (1007-1011), and13A (1001) with results plotted as RLU reported on the y-axis and SARDconcentration on the x-axis (nM). In these Figures, antagonist mode datawas shown as curve fitted data, whereas agonist mode data (if present)is reported without curve fitting. Only weak and partial agonism wasseen. In vivo pharmacodynamics demonstrate potent and highly efficaciousantagonism of androgen dependent tissues (see Examples 7 and 10 herein).FIG. 2 is a direct comparison of antagonism between 11 (closed dots) and1002 (open dots). Other IC₅₀ values reported in Table 1 were calculatedby the same method.

1002 was a potent antagonist (199.36 nM; Table 1 and FIG. 1A) withcomparable inhibition as 11 (85.1 nM; FIG. 2) which is an extremelypotent indole SARD lacking oral bioavailability. Despite the 2-foldincreased IC₅₀ (Table 1) and lack of AR-LBD binding (see Example 4 andTable 1), 1002 was a more potent AR degrader in vitro (see Example 5 andTable 1). Further and unlike 11, 1002 was very stable in vitro in mouse(Table 1) and human liver microsomes (Table 2) which translated intoimproved in vivo pharmacodynamics (see Example 7 herein) in mice andrats. Based on the structural differences alone, the increased SARDactivity in vitro and metabolic stability were each unexpected results.Likewise, the greatly improved in vivo efficacy could not have beenpredicted (i.e., was unexpected) based on structural differences alone.1012, 1014, and 1017 also demonstrated improved metabolic stability invitro suggesting that the pyrazole moiety may be responsible for theunexpected stability of 1002.

As discussed below, 1002 and 1014 also demonstrated significantanti-tumor activity in in vivo xenograft studies (see Examples 8 and10), suggesting that the bioavailability of these compounds issufficient for their intended uses.

1004 (pyrrole) and 1006 (imidazole) demonstrated potent inhibition(178.77 nM and 148.94 nM; Table 1; FIGS. 4A and 6A) but weak SARDactivity, whereas 1005 and 1016 demonstrated weak inhibition but strongSARD activity, suggesting that in vitro inhibition is not wellcorrelated with SARD activity. However, 1010 (pyrrole), 1012 (pyrazole),and 1014 (pyrazole) were potent inhibitors and degraders. In general,LBD binding or LBD-dependent inhibition and in vitro SARD activity seemto be separate but highly tolerant structure activity relationships.Values for other compounds of the invention are reported in Tables 1 and2.

Potent inhibition of transactivation was also seen for 1020 (192 nM),1022 (92 nM), and 1024 (464 nM). 1020 is an R-isomer of pyrazole 1002,and like 1002, does not bind to the LBD yet has strong SARD activity.Similarly, the indole SARD 11 and the R-isomer of 11 have comparableSARD activities (Table 1 and FIG. 2B) for AR-FL (LNCaP) and AR-SV(22RV1). This is in sharp contrast to propanamide SARMs such asenobosarm which typically have 100-fold lower LBD binding and agonistactivity for R-isomers (data not shown). This is further evidence thatSARD activity is not mediated through the LBD, as will be discussed inmore detail in Example 9 below. Example 9 demonstrates a novel bindingsite in the N-terminal domain (NTD), providing a basis for the distinctstructure activity relationships from traditional AR antagonists thatbind to the LBD and SARD of this invention which act through the NTD.The retention of SARD activity in opposite isomers (unlike SARMs)suggests that the NTD binding site does not require stereospecificity inits ligands. Further, the NTD binding site does not seem to require thechiral hydroxyl group which is conserved for LBD-binding (agonists and)antagonists. E.g., 1024 is a non-chiral propanamide racemate which lacksthe hydroxyl but retains SARD activity (Table 1: 60% degradation ofAR-FL) and the ability to inhibit the AR (Table 1: IC₅₀=464 nM) despitenot binding the LBD (Table 1: K_(i): no binding). Also, 1029 replacesthe chiral center with a methylene group and yet retains some SARDactivity (Table 1: 35% degradation of AR-FL) and AR antagonism (Table 1:IC₅₀=2124 nM). 1032 has its hydroxyl group protected by acylation andand does not bind the LBD yet is an antagonist of AR. Another possibledivergence in SAR's is the A-ring which is conserved for LBD binders as4-cyano or nitro and 3-trifluoromethyl or 3-chloro. However, changingthe CF₃ of 1002 to the Cl of 1007 ablated SARD activity. Further, 1022has a novel pyridine A-ring and does not bind to the LBD yet retainspotent inhibition of transactivation (92 nM) and SARD activity (Table1). Similarly, SARD activity is shown for 1037 and 1041 that containpyridine A-rings (Table 1 and FIG. 28C), and 1043 is a highly potentpyridine antagonist but weak SARD activity (Table 1). Further, 1037 is a3-bromopropanamide (i.e., lacks a heterocyclic B-ring) which bindsweakly to the LBD (4547 nM) but is a potent antagonist (350.5 nM) andretains SARD activity, demonstrating that the B-ring may not benecessary (Table 1) for SARDs of this invention. Such observationsconfirm that SARD activity can be optimized in the absence of LBDbinding data and provide a rationale for the degradation of AR splicevariants lacking the LBD.

Example 4 Human Androgen Receptor (hAR) Ligand Binding Domain (LBD)Affinity Assay

Methods:

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant AR-LBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (K_(d)) of [³H]mibolerone. Protein was incubated withincreasing concentrations of [³H]mibolerone with and without a highconcentration of unlabeled mibolerone at 4° C. for 18 h in order todetermine total and non-specific binding. Non-specific binding was thensubtracted from total binding to determine specific binding andnon-linear regression for the ligand binding curve with one sitesaturation was used to determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR-LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BiogelHT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail.

Results:

The results of this assay are reported as K_(i) values (nM) in Table 1in the column labeled ‘wt AR Binding (K_(i) (left))’. As discussed aboveand is apparent from Table 1, there is a poor correlation between AR-LBDaffinity and SARD activity. E.g., see in vitro SARD activity for 1002,1005, 1015, 1019, 1020, and 1022 despite no binding affinity for the LBD(Table 1).

Example 5 In Vitro Assays to Determine SARD Activity

LNCaP or AD1 Androgen Receptor Degradation (Full Length AR):

The compounds of the invention were tested for their effect on fulllength AR protein expression. Methods: LNCaP or AD1 cells expressingfull length AR were plated at 750,000-1,000,000 cells/well of a 6 wellplate in growth medium (RPMI+10% FBS). Twenty four hours after plating,the medium was changed to RPMI+1% csFBS without phenol red andmaintained in this medium for 2 days. The medium again was changed toRPMI+1% csFBS without phenol red and cells were treated with SARDs (1 nMto 10 mM) in combination with 0.1 nM R1881. After 24 h of treatment,cells were washed with cold PBS and harvested. Protein was extractedusing salt-containing lysis buffer with three freeze-thaw cycles. Theprotein concentration was estimated and five microgram of total proteinwas loaded on a SDS-PAGE, fractionated, and transferred to a PVDFmembrane. The membrane was probed with AR N-20 antibody (SantaCruzBiotechnology, Inc., Dallas, Tex. 75220) and actin antibody(Sigma-Aldrich, St. Louis, Mo.).

Results:

Degradation in LNCaP or AD1 cells are reported in Table 1 in the columnlabeled ‘Full Length % Inhibition at 1, 10 μM’. The results of thisassay were reported in FIGS. 1B (1002), 2B (11, 11R, 1002, 1020), 3B-6B(1003-1006), 7 (17), 13B (1001), 20A (1010, 1012, 1014, 1015, 1017, 1019and 1022), 28A (1024 and 1029), 28C (1037 and 1041), 28D (1044 and 1045)as images of Western blot films (chemiluminescence exposed films).

22RV1 or D567es androgen receptor degradation (splice variant (S.V.)AR): The effect of SARD treatment on the AR levels was measured inandrogen-refractory 22RV-1 or D567es prostate cancer cells. Methods:22RV1 or D567es cells expressing AR splice variants (AR-SV) were platedat 750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed andtreated. After 24-30 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree freeze-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody (Santa Cruz Biotechnology, Inc., Dallas, Tex. 75220) and actinantibody (Sigma-Aldrich, St. Louis, Mo.).

Results:

Degradation in 22RV1 or D567es cells are reported in Table 1 in thecolumn labeled “S.V. % inhibition at 10 μM.” The results of this assayin D567es cells were reported in FIGS. 1C (1002) and 20B (1010, 1012,1014-1017, 1019 and 1022), and in 22RV1 cells in FIGS. 2B (11, 11R), 13C(1001), and 28B (1024 and 1029) as images of Western blot films(chemiluminescence exposed films).

Example 6 Metabolism Studies with Mouse Liver Microsomes (DMPK (MLM))Determination of Metabolic Stability (In Vitro CL_(int)) of TestCompounds: Phase I Metabolism

The assay was done in a final volume of 0.5 mL in duplicates (n=2). Thetest compound (1 mM) was pre-incubated for 10 minutes at 37° C. in 100mM Tris-HCl, pH 7.5 containing 0.5 mg/mL liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes). 100 mLaliquots were removed and quenched with 100 mL of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 min. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As a control, sampleincubations done in the absence of NADPH were included. From % PCR (%Parent Compound Remaining), rate of compound disappearance wasdetermined (slope) and in vitro CL_(int) (μl/min/mg protein) wascalculated.

Results:

FIG. 14 reported phase I data as a raw data table for one experiment inMLM for compound 1002 and the T_(1/2) (half-life) and CL_(int)(clearance) values calculated therefrom. FIGS. 15A and 16A report phaseI data as a raw data table and graphed data for one experiment for 1002in mouse liver microsomes (MLM) and human liver microsomes (HLM),respectively. Similarly, FIG. 17 reported MLM data for 1001 and theT_(1/2) (half-life) and CL_(int) (clearance) values in Tables 1 and 2were calculated therefrom.

Metabolic Stability in Phase I & Phase II Pathways

In this assay, the test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tosimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin were included in the assay. From % PCR (% Parent CompoundRemaining), rate of compound disappearance is determined (slope ofconcentration vs. time plot) and in vitro CL_(int) (μl/min/mg protein)was calculated. The results of this assay utilizing mouse livermicrosomes (MLM) are reported in Table 1 in the column labeled “DMPK(MLM) T½ (Min) & CL_(int) (μL/min/mg)”. The first value is thecalculated half-life (Tire) of the test article in MLM expressed inminutes and the 2^(nd) value is the intrinsic CL (CL_(int)) of the testarticle in MLM expressed as mL/min/mg protein.

Results:

FIG. 14 reported phase I & II data as a raw data table for oneexperiment and the T_(1/2) (half-life) and CL_(int) (clearance) valuescalculated therefrom. FIG. 15B (using mouse liver microsomes (MLM)) and16B (using human liver microsomes (HLM)) reported phase I & II data for1002 as a raw data table for separate single experiments and grapheddata. This data demonstrated that 1002 is stable in MLM and very stablein HLM. The LC-MS/MS analysis was performed as described below.

The metabolic stability of 1002 and other pyrazoles of this inventionwas unexpected in view of previous SARDs (100, 17, & 11; see Table 1).See also Examples 8 and 10 for comparisons of pyrazoles to previous SARDtemplates and their unexpected results in terms of metabolicstabilities, in vivo pharmacodynamics, in vivo serum and tumorconcentrations, and in vivo anti-tumor efficacies in advanced prostatecancer (Example 10) and triple negative breast cancer (Example 8).Further, MLM data for 1024 (Table 1), a non-hydroxy variant, and 1023, apyridine A-ring compound (non-carbonitrile), both revealed a lack ofmetabolism after incubation with MLM for 60 minutes. This demonstratesmetabolic stability of SARDs of this invention including those withpyrazole B-rings, that lack the hydroxyl group, and/or includealternative A-rings.

LC-MS/MS Analysis:

The analysis of the compounds under investigation was performed usingLC-MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000Q-Trap™ mass spectrometer. The separation was achieved using a C₁₈analytical column (Alltima™, 2.1×100 mm, 3 μm) protected by a C₁₈ guardcartridge system (SecurityGuard™ ULTRA Cartridges UHPLC for 4.6 mm IDcolumns, Phenomenex). Mobile phase was consisting of channel A (95%acetonitrile+5% water+0.1% formic acid) and channel C (95% water+5%acetonitrile+0.1% formic acid) and was delivered at a flow rate of 0.4mL/min. The volume ratio of acetonitrile and water was optimized foreach of the analytes. Multiple reaction monitoring scans were made withcurtain gas, collision gas, nebulizer gas, and auxiliary gas optimizedfor each compound, and source temperature at 550° C. Molecular ions wereformed using an ion spray voltage of −4200 V (negative mode).Declustering potential, entrance potential, collision energy, production mass, and cell exit potential were optimized for each compound.

Example 7 In Vivo Antagonism Demonstrated by SARD Compound 1002

Hershberger Method:

Male mice (20-25 grams body weight; n=5-7/group) were either left intactor castrated and treated as indicated in the figures for 13 days.Treatment of castrated mice was initiated 3 days after castration. Micewere sacrificed on day 14 of treatment and seminal vesicles were removedand weighed. Seminal vesicles weights were either represented as is orwere normalized to body weight and represented.

Results:

1002 significantly reduced the weight of seminal vesicles at 40 mg/kgoral daily dose in intact (FIG. 18A) and 100 mg/kg in castrated (FIG.18B). The reduction in seminal vesicles weight, which is representativeof androgen receptor (AR) antagonism, was more pronounced than that ofthe 20 mg/kg/day enzalutamide dose. 1002 was effective even in castratedmice, indicating that even any residual AR activity in castratedAR-target tissues was further inhibited by the potent activity of 1002which bodes well for the abilities of SARDs of this invention to treatADT-treated prostate cancer patients. This suggests that even thoughsome weak partial AR agonism is observed in in vitro transactivationexperiments, the predominant tone in vivo is AR antagonism. Further, invivo activity at 40 mg/kg (40 mpk) for 1002 was a dramatic improvementover previously tested SARDs from our laboratory which typically onlyproduced in vivo effects at 100 mg/kg or more despite comparable invitro transcriptional inhibition potencies. This suggests the unexpectedmetabolic stability of 1002 translated into clinically significant oralbioavailability.

The Hershberger experiments were repeated in rats since rats are knownto be more sensitive models of androgenic and anabolic activities of ARagonists and antagonists. Sprague Dawley rats (165-180 gms) body weightwere treated with vehicle, 40 mpk 1002, 60 mpk 1002, or 20 mpkenzalutamide orally. After 13 days of treatment, the rats weresacrificed and the weights of prostate, seminal vesicles, and levatorani were measured. 1002 at 40 mg/kg antagonized the weights of seminalvesicles, prostate and levator ani muscle to approximately the sameextent as 20 mg/kg enzalutamide and 60 mg/kg 1002 further suppressed theweights of each of these tissues to near castration levels (FIG. 19A).FIG. 19A shows the reductions in absolute organ weights in intact ratsand FIG. 19B represents the same data of % inhibition relative tovehicle treated control. The bottom right panel of FIG. 19B presents theeffect of castration on the weights of seminal vesicles and prostate.1002 at 60 mg/kg reduced prostate and seminal vesicles weights by ˜70%each compared to 90% and 85% reductions, respectively, produced bycastration (not shown). 1002 is the first SARD with sufficientbioavailability to produce in vivo AR antagonism in excess ofenzalutamide despite inferior in vitro potencies in transactivation(IC₅₀) and a lack of binding to LBD (K_(i)). 1002 possesses potent SARDdegradation activities in vitro. Correspondingly, the unexpectedlysuperior in vivo antagonism of 1002 compared to enzalutamide (the IND ofenzalutamide indicated that 100 mpk and 30 mpk had comparable in vivoefficacy, so the 20 mpk dose presumably was near E_(max) and was barelysoluble) is not explainable in terms of conventional inhibition of theAR through the LBD but rather suggests that the AR antagonism isattributable to the potent degradation of the AR which is a uniqueproperty to compounds of this invention.

See also Example 9 for multiple biophysical lines of evidence supportingNTD binding of 1002 and other SARDs of this invention. See also Example10 for unexpected results for 1014 in a Hershberger assay, and other invivo assays.

Example 8 In Vivo Anti-Tumor Activity Demonstrated by SARD Compound 1002in Triple Negative Breast Cancer (TNBC) Patient Derived Xenografts (PDX)

Patient Specimen Collection and PDX Creation:

Specimens from breast cancer patients were collected with patientconsent under a protocol approved by the University of Tennessee HealthScience Center (UTHSC) Institutional Review Board (IRB). Briefly,specimens were collected immediately after surgery in RPMI mediumcontaining penicillin:streptomycin and Fungizone (Thermo FischerScientific) and transported to the laboratory on ice. The tissues wereminced finely and treated with collagenase for 2 h. The digested tissueswere washed with serum-free medium and implanted as 1 mm³ fragmentssubcutaneously in female Nod Scid Gamma (NSG) mice. Two such PDX fromtriple-negative patients (TNBC), HBrT-1071 and HBrT-1361, characterizedas TNBC at the time of collection, were implanted in ovariectomizedmice. All animal studies were conducted under the UTHSC Animal Care andUse Committee (ACUC) approved protocols. Female NSG mice (6-8 weeks old)purchased from JAX labs (Bar Harbor, Me.) were housed as five animalsper cage and were allowed free access to water and commercial rodentchow (Harlan Teklad 22/5 rodent diet—8640). HBrT-1071 and HBrT-1361 wereimplanted (1 mm³) under the mammary fat pad surgically under isofluoraneanesthesia. Once tumor sizes reached 100-200 mm³, the animals wererandomized and treated with vehicle (polyethylene glycol-300: DMSO 85:15ratio) or 1002 (60 mg/kg/day p.o.). Tumors were measured thrice weeklyusing caliper and the tumor volume was calculated using the formulalength*width*width*0.5236. At the end of the experiments, animals weresacrificed, tumors were weighed and collected for further processing.Blood was collected, serum was separated, and stored in −80° C.

Results:

The SARD compound 1002 was able to inhibit tumor growth in two differentTNBC PDX models (FIGS. 21A and 21B) whereas enzalutamide failed toinhibit tumor growth (FIG. 21A). 1002 significantly inhibited the growthof HBrt 1071 TNBC PDX with a percent tumor growth inhibition of 65%.Similarly, 1002 inhibited the tumor weight by over 50% (FIG. 21A). Incontrast, tumors from enzalutamide treated animals wereindistinguishable in size from vehicle treated animals, or possiblytrended toward promoting tumor growth. 1002 significantly inhibited thegrowth of HBrt-1361 TNBC PDX with a percent tumor growth inhibition of−50% and inhibited the tumor weight by over 40% (FIG. 21B). Further,analyses of the AR which was present in these tumors revealed highlevels of AR splice variants (FIG. 21A, lane labeled 1071). Thisobservation helps to rationalize why 1002, an NTD-binding SARD (seeExample 9 below for biophysical evidence of NTD binding), was able toinhibit tumor growth whereas the LBD-dependent AR antagonistenzalutamide failed. This suggests that SARDs are able to inhibit ARsplice variant dependent cancers such as TNBC and advanced prostatecancers (see Example 10), e.g. those expressing AR-V7 or other AR'slacking the LBD. Further, this is confirmation that the unexpected oralbioavailability of 1002 and other SARDs of this invention, e.g. 1014 and1010, allowed serum and tumor (see also Example 10) levels followingoral administration to be sufficient for treatment of advanced andrefractory AR-dependent cancers.

Example 9 SARDs Bind to AF-1 Region of the N-Terminal Domain (NTD) ofthe Androgen Receptor

Nuclear Magnetic Resonance (NMR):

AF-1 and various fragments of AF-1 were cloned in pGex4t.1 and pGex6p.1vectors. To purify proteins, large scale Luria broth cultures wereinduced with 1 Mm isopropyl β-D-1-thiogalactopyranoside (IPTG) when theO.D. reached 0.6 and incubated at 25° C. for 6 h. Cells were harvestedand lysed in a lysis buffer (50 mM Tris pH 7.5, 25-250 mM NaCl, DNase,protease inhibitors, glycerol, EGTA, DTT, and sucrose). Protein lysateswere purified using glutathione sepharose beads by incubating overnightat 4° C. with gentle rocking and the purified protein was eluted withelution buffer (lysis buffer without DNase) containing 50 mM reducedglutathione. Purified proteins were concentrated using Amicon or GEprotein concentrators. In cases where GST needed to be cleaved,PreScission Protease (GE Life Sciences) was used to cleave the GST. Theproteins were further purified using FPLC (GE AKTA FPLC) with gelfiltration (Superdex75 10/300 GL) and ion exchange (HiPrep Q FF 16/10)columns. Compounds alone or in combination with purified protein wererun in ¹H NMR (Bruker 400) in a total volume of 500 μL with 5 mM proteinand 200-500 mM small molecule (made in deuterated DMSO (DMSO-d₆)) in 20mM phosphate buffer made in 100% deuterated water.

NMR data were collected using a Bruker AVANCEIII 400 MHz NMRspectrometer (Bruker BioSpin Co. Billerica, Mass. USA) equipped with aBBO 5 mm NMR probe, and TopSpin 3.0 software. ¹H proton NMR andSaturation-Transfer Difference (STD) experiments were acquired usingstandard pulse sequences in the TopSpin library. Spectral width was setto 16 ppm with H₂O peak at center. 32K time domain (TD) complex datapoints and 256 scans were used for ¹H proton NMR and 1024 scans for STDacquisition. For STD, on- and off-resonance [signals] were collectedusing interleaved method. Irradiation frequencies for on- andoff-resonance were set at 0.8 ppm and −20 ppm, respectively. STD wasacquired on a sample with ligand compound alone using identical settingsto make sure the STD signals originated from protein in theprotein-compound complex sample. Data were collected at roomtemperature. Chemical shift was referenced according to H₂O peak at 4.70ppm.

Results:

¹H NMR has been used in high-throughput screens to detect the binding ofsmall molecules less than 500 Da to large proteins greater than 5 Kda.As opposed to other biophysical methods, it is easier to use onedimension NMR to observe changes in line-width or line broadening as ahigh-throughput method to identify the binding of the molecules toproteins and then use Water ligand-observed spectroscopy (WaterLOGSY) orSaturation-Transfer Difference (STD) NMR as confirmatory methodologies.These experiments are based on the fact that NMR observables such aslinewidths and NOEs vary dramatically between small molecules and largemolecules. The decreased rotational correlation times upon binding of asmall molecule ligand to a heavy target molecule produces an atypicalheavy molecule NMR result characterized by broadening and weakening ofligand peaks in ¹H NMR and negative NOE peaks in the waterLOGSY ascompared to the free state. In the absence of any affinity, the smallmolecule NMR result is obtained (sharp peaks in ¹H NMR and positiveNOEs) even in the presence of target protein. This distinction providesthe basis for NMR screening experiments.

Using these principles, ¹H NMR was utilized to confirm the binding of1002 to the AF-1 region. 1002 (500 mM) was dissolved in deuterated DMSO(DMSO-d₆) and was incubated alone or mixed with 5 mM AF-1 and thebinding of the molecules to the protein was determined by NMR. While1002 alone exhibited sharp peaks revealing the ligand present in thefree state, 1002 in combination with AF-1 provided broad, diffused, andshorter ligand peaks revealing that 1002 has affinity for AF-1 (FIG.22). To further confirm the 1D NMR results, we performed WaterLOGSY with1002 alone or in combination with AF-1. While the 1002 alone gave aflattened positive signal, 1002 in combination with AF-1 provided anegative signal, characteristic of binding to the protein (FIG. 22).These results provide evidence that 1002 binds to AF-1 in the NTD of AR,explaining how a molecule that does not bind the LBD of AR (Table 1) caninhibit the AR in vitro and in vivo.

Steady State Fluorescence:

Recombinant histidine tagged AR-NTD (amino acids 1-559) and AR-AF1(amino acids 141-486) were purified as previously described. Thesteady-fluorescence spectrum for the proteins (1 μM) alone or aftertitration with increasing concentrations of 1002 (1 μM, 2 μM, 5 μM, 10μM, 25 μM, & 50 μM) was measured after excitation at 278 nm on aShimadzu Fluorescence spectrophotometer. Proteins were preincubated onice for 30 minutes with 1002. The results represent three independentexperiments (n−3) measured in duplicate.

Results:

The pyrazole SARD 1002 showed a dramatic increase in the fluorescencesignal in the region seen for tyrosine emission (FIG. 27B, 307 nm).Normally, the tyrosine signal is not seen due to energy transfer totryptophan residues in folded/partially folded polypeptides. Theincrease in the tyrosine signal is similar to what is seen inunfolded/denatured AR-NTD or AR-AF1, e.g., upon addition of urea (FIG.27A). However, there is no corresponding ‘red shift’ (increase inwavelength) in the tryptophan signal (compare FIGS. 27A and 27B, in ureaλ_(max) 344 nm to 347 nm). 1002 may unfold the receptor polypeptides(resulting in tyrosine emission), but shield the tryptophan residues.

For the pyrrole SARD 1010, some evidence for quenching was observed, butthe concentration dependence was poor. However, more strikingly therewas a consistent and dramatic ‘blue shift’ (toward smaller wavelengths),which was consistent with the folded form of AR-NTD/AF (i.e. TMAOspectrum in FIG. 27C, λ_(max) 344 nm to 340 nm). On the basis of data sofar it seems 1010 may stabilize the structure of the AR polypeptides.The data with the indole SARD 36 (FIG. 27D) was similar to what was seenwith 1002, but the changes in fluorescence were weaker. In each case, aninteraction was observed between the SARD and the AR-1 or NTD. Thoughthe perturbation of fluorescence polarization (FP) was not identical,these similar results across multiple templates of SARDs suggest thatthe interaction with the N-terminus of the androgen receptor is aconserved feature for the SARDs of this invention. Further, 1002 lacksan interaction with the LBD yet retains potent AR antagonism and SARDactivity.

Example 10 Metabolic Stability of Pyrazoles Such as 1014 and 1002Reveals the Therapeutic Potential of SARDs In Vivo In VitroCharacteristics:

Transactivation (IC₅₀):

As reported in Table 1 using the method of Example 3, 1014 is a potentinhibitor of the AR with an IC₅₀ value of 205 nM which is similar to1002 (199 nM).

LBD binding (K_(i)):

As reported in Table 1 using the method of Example 4, 1014 binds to theLBD of the AR with a K_(i) value of 512 nM, whereas 1002 does not bindto the LBD.

SARD Activity:

As reported in Table 1 using the methods of Example 5, 1014 and 1002 arecapable of potently degrading full length and splice variant androgenreceptors.

LNCaP-Enzalutamide Resistant (LNCaP-EnzR) Cells MR49F Growth Assay:

Cells were plated at 10,000 cells/well in RPMI+1% csFBS without phenolred medium in 96 well plates. Cells were treated in the indicated mediumwith a dose response of the SARDs. At the end of three days, medium waschanged and the cells were re-treated. At the end of 6 days, the livecells were measured by Cell-Titer-Glo (Promega) assay.

Results:

1002 and 1014 demonstrated comparable growth inhibition of anenzalutamide resistant variation of the LNCaP (LNCaP-EnzR) cell linewhich bears the double mutant F₈₇₆L/T877A, conferring resistance toenzalutamide. 1002 and 1014 both had IC₅₀ values of ˜3 μM and almostcomplete inhibition at 10 μM (FIG. 23), suggesting that either SARDcould be beneficial for enzalutamide resistant prostate cancer patientsif these levels could be achieved in the tumor. (see Table 4 below)

Liver Microsome Metabolism Study:

Materials:

Microsomes were purchased from Xenotech, LLC. Solution ‘A’ and ‘B’ (Cat#451220, and 451200, respectively) for NADPH regenerating system (NRS)solution were obtained from Corning Life Sciences. Verapamil, genistein,UDPGA, alamethicin and magnesium chloride were purchased fromSigma-Aldrich. Saccharolactone was obtained from Santa CruzBiotechnology.

Method: Phase I

Test compound stock solutions were prepared at 10 mM in DMSO. They werediluted to a concentration of 50 μM in 50% acetonitrile (ACN)/H₂Oresulting in a working stock solution of 100×. Liver microsomes wereutilized at a final concentration of 1.0 mg/mL of protein. Duplicatewells were used for each time point (0, 5, 10, 30, and 60 minutes).Reactions were carried out at 37° C. in a shaking water bath, and thefinal concentration of solvent was kept constant at 0.5%. At each timepoint, 100 μL, of reaction was removed and added to a sample wellcontaining 100 μL, of ice-cold, 100% ACN (plus internal standard), tostop the reaction. The final volume for each reaction was 200 μL,composed of: 66 μL of 0.2 M KPO₄ buffer, (pH 7.4); 50 μL of NRSsolution; and 10 μL of microsomes (20 mg/mL stock).

The NRS is a solution of glucose-6-phosphate dehydrogenase, NADP⁺,MgCl₂, and glucose-6-phosphate, prepared per manufacturer'sinstructions. Each 5.0 mL stock of NRS solution contains 3.8 mL H₂O, 1.0mL solution “A”, and 0.2 mL solution “B”. The reaction from the positivecontrol wells (verapamil, 0.5 μM) were stopped with ice coldacetonitrile containing internal standard.

Phase I and II

Reaction conditions were followed similarly as described above.Additional cofactors were also included in each reaction. UDPGA wasadded at a final concentration of 5.0 mM. Saccharolactone(β-glucuronidase inhibitor) and alamethicin (pore forming peptide) wereadded to each reaction at a final concentration of 5.0 mM and 50 μg/mL,respectively. Each 200 μL of microsomal reaction was comprised of 65 μLof 0.2 M KPO₄ (pH 7.4), 50 μL of NRS mixture, 66 μL of UDPGA (15 Mmstock); 5.0 μL of saccharolactone (200 mM stock); 0.5 μL of alamethicin(20 mg/mL); 0.6 μL of MgCl₂ (1 M stock), and 10 μL of microsomes (20mg/mL stock). The reaction from the positive control wells (genistein,2.0 μM) was stopped with ice cold acetonitrile containing internalstandard.

Samples were centrifuged at 3,000 rpm for 10 minutes to remove debrisand precipitated protein. Approximately 150 μL of supernatant wassubsequently transferred to a new sample block for analysis.

Data Analysis

For half-life determination and clearance, data was fitted usingGraphPad Prism with a non-linear regression equation, and one phaseexponential decay.

Results:

1014 was compared to other compounds, including 1002 in liver microsomemetabolism studies. Interestingly, while 1002 showed a half-life around1 h in vitro, 1014 had a half-life of infinity in the same test, i.e.,after 120 min of incubation over 50% of the compound still remained inthe reaction (Table 3). As seen in Table 3, the pyrazoles 1002, 1014,and 1022 (see also Table 1 for 1023 and 1024) demonstrated much improvedin vitro metabolic stabilities compared to indole (11, 34, 36) andindoline (103) based compounds (and the pyrrole 1010) (Table 3) whileretaining SARD activity (Table 1). This suggested that significant invivo bioavailabilities may be possible for 1002 and 1014.

TABLE 3 Liver microsomes MLM/RLM t_(1/2) CL_(int) (min) (μL/min/mg) 100277.96 0.89 1014 infinity ~0 96 54.44 12.73(S)-N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-(trifluoromethyl)-1H- indazol-1-yl)propanamide1010 17.93 38.66 36 11.77 58.8(S)-N-(3-Chloro-4-cyanophenyl)-3-(4-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide 34 15.50 58.87(S)-N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-hydroxy-2- methylpropanamide 11 14.35 48.30(S)-N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indol-1-yl)-2-hydroxy-2- methylpropanamide 103 15 46.22(S)-N-(3-Chloro-4-cyanophenyl)-3-(4- fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide 1022 58.06 11.94

In Vivo Characteristics:

1014 Drug Concentrations in Serum and Tumor in a Xenograft Experiment:

Nude mice implanted with 22RV1 cells subcutaneously were randomized whenthe tumors reached between 100 and 200 mm³. The mice were treated withvehicle (20:80 water:PEG-400) or 60 mg/kg/day 1014 (or indicated dosesof other SARDs) in vehicle for 21 days. At the end of 21 days, the micewere sacrificed and blood and tumors were collected for furtheranalysis. Measurement of drug concentration in animals treated with 1014demonstrated a significant accumulation of the drug in serum (20.1 μM)and tumor (35.6 μM) (Table 4 and FIG. 24) compared to other moleculestested in parallel in the same experiment. These in vivo levels for1014, even in view of structurally similar pyrazoles 1002 and 1012, wasunexpected. Further, these levels help to explain the efficacy inLNCaP-EnzR xenografts (see FIG. 26 and its description below). Although22RV1 tumors were not susceptible to SARDs in this particularexperiment, likely due to androgen independent growth, this resultsuggests that androgen-dependent tumors, e.g., LNCaP-EnzR, would besusceptible. Another observation from these data is that tumorconcentrations were in excess of serum concentrations, suggestingaccumulation of drug in the tumor. The results are shown in Table 4 andFIG. 24.

TABLE 4 Tumor Xenograft PK Xenograft concentration Serum concentrationdose (nM) (nM) (mg/kg) At sacrifice (8 hrs) 2 hrs 8 hrs 1002 60 15,7253,560 3,620 11 100 854 365 338 1012 60 6,655 2,114 1,914 1014 60 35,6384,469 20,119 96 100 4,458 1,207 2,563 1010 100 17,683 862 4,173 103 1001,748 380 1,776 36 100 7,128 570 4,142 34 100 2,948 261 965

Hershberger Assay:

Intact C57BL/6 male mice (6-8 weeks old) were randomized based on bodyweight and treated with various compounds indicated in FIG. 25 for 14days. At the end of 14 days, the mice were sacrificed and seminalvesicles were weighed. 1014 demonstrated the best inhibition of seminalvesicles weight compared to other compounds, following by 1002,suggesting that these orally administered SARDs were present in levelssufficient to antagonize the AR in androgen-dependent tissues of intactanimals. The indoles 34 and 36, pyrrole 1010, and the pyrazole 1012 didnot exhibit strong AR antagonism in vivo in this assay.

LNCaP-Enzalutamide-Resistant (LNCaP-EnzR) Xenograft:

LNCaP-EnzR cells MR49F in RPMI+10% FBS were mixed with Matrigel (BDBiosciences) (1:1) and injected subcutaneously in NOD SCID Gamma (NSG)mice (100 μL). Once the tumors reached 100-200 mm³, the animals wererandomized and were treated with vehicle (20:80 water:PEG-300) or 1014(60 mg/kg/day) in vehicle. Tumor volume was measured twice weekly. Atthe end of the study, animals were sacrificed, tumors isolated, weighed,and stored for further analysis. The experiment was performed twice withtwo different batches of cells and the results are shown in FIG. 26.Results: In two separate experiments, 1014 was able attain high efficacytumor growth inhibition, reducing tumor volumes by approximately 60-70%compared to vehicle treated animals. These results suggest that 1014 andother SARDs of this invention administered orally were capable oftherapeutic efficacy in enzalutamide resistant (i.e., advanced andrefractory) prostate cancers.

Conclusion:

All these results indicate that 1014 has unexpected properties due toits slow metabolism and tumor accumulation. Although, 1014 structurallyis comparable to 1002, only differing slightly in the substitution witha CF₃ in the third position of the pyrazole ring (vs. 4-fluoro for1002), it is extremely resistant to metabolism by liver microsomes andthereby has significant accumulation in serum, androgen dependentorgans, and in tumors which is unexpected in view of other SARDs testedand in the prior art. This allowed for unexpected in vivo efficaciesfollowing oral administration, such as pharmacodynamics (Hershbergerassay demonstrated most efficacious seminal vesicles weight effect seenwith a SARD) and xenograft tumor growth inhibition (LNCaP-EnzRxenograft), that would not have been possible with our earlier reportedSARD templates such as 11, 100, and 17, or other SARDs known in theprior art.

Example 11 SARDs Antagonize F876L

FIGS. 29A-29C illustrate that SARDs antagonized F876L AR at dosescomparable to the wildtype AR and do not have any intrinsic agonistactivity in F876L, showing their ability to overcome enzalutamideresistance. In FIGS. 29A-29C, compound 1002 was able to inhibit thetranscriptional activation of wtAR and F876L (enzalutamide resistance)and W741L (bicalutamide resistance). Enzalutamide behaved similarly,however enzalutamide acted as an agonist at higher levels of treatmentof F876L. This demonstrated the ability of SARDs to overcome antagonistswitch mechanisms of resistance which are prevalent in CPRC. Further,Example 10 shows the ability of SARDs to overcome enzalutamideresistance with regard to cellular growth and with regard to xenograftgrowth.

Example 12 Binding to AR-NTD to Degrade

FIG. 32 shows that AR NTD binding of 1002 for required for degradation.Chimeric constructs were created in which the AR and GR were cloned suchthat the entire sequence was AR or GR, or the N-terminal domain wasderived from AR but the DNA binding and ligand binding domains werederived from GR (AGG) or vice versa (GAA). Several lines of evidencesummarized below suggested either NTD binding and/or dependence upon NTDfor SARD activity. Further to that line of reasoning, the SARD 1002 wastested for its ability to degrade the AR, GR, AGG or GAA constructs as away to demonstrate that AR NTD was required in order for the SARD todegrade the protein (i.e., demonstrate NTD-dependence). Other lines ofevidence suggesting NTD-dependent SARD activity included: FIGS. 22 (NMR)and 27 (fluorescent polarization) demonstrated 1002 binding to NTD andtheir ability to degrade SV's which lack any LBD further suggested NTDbinding. Example 3 discusses potent transcriptional activity in theabsence of demonstrable LBD binding and structure-activity relationshipsof NTD binding that differ from known LBD SAR patterns. Example 8discusses the ability of 1002 to inhibit SV-driven growth (i.e., FL ARis not expressed) of TNBC xenografts with SARD 1002, suggesting NTDbinding. Consistent with this interpretation, the LBD-dependent ARantagonist enzalutamide failed to inhibit TNBC xenograft growth in thesesame TNBC xenografts.

The chimeric receptor data as provided in FIG. 32 is a strong evidencefor NTD-dependence of SARD activity. From the Western blots of FIG. 32,it is apparent that SARDs degraded AR and/or AGG (NTD is AR and rest isGR) but not GR or GAA (NTD is GR and rest is AR). This suggests that ARNTD is required for SARD activity.

Example 13(S)-3-(4-Bromo-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂BrF₃N₄O₂) (1050)

To a solution of 4-bromo-1H-pyrazole (0.20 g, 0.0013608 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.16g, 0.0040827 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.478 g, 0.001608 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at roomtemperature under argon. The reaction was quenched by water andextracted with ethyl acetate. The organic layer was washed with brine,dried with MgSO₄, filtered, and concentrated under vacuum. The productwas purified by a silica gel column using DCM and ethyl acetate (19:1)as eluent to afford 0.47 g (79.6%) of the titled compound as white foam.

¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H, NH), 8.00 (d, J=2.0 Hz, 1H, ArH),7.87 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 7.79 (d, J=8.4 Hz, 1H, ArH),7.49 (s, 1H, Pyrazole-H), 7.47 (s, 1H, Pyrazole-H), 5.92 (s, 1H, OH),4.64 (d, J=14.0 Hz, 1H, CH), 4.24 (d, J=14.0 Hz, 1H, CH), 1.47 (s, 3H,CH₃).

Mass (ESI, Negative): 371.68 [M−H]⁻; (ESI, Positive): 440.94 [M+Na]⁺.

(R)-3-Bromo-N-(4-cyano-2-iodo-5-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₂H₉BrF₃IN₂O₂) (1051)

3-Bromo-2-methyl-2-hydroxypropanoic acid (0.50 g, 0.00273224 mol) wasreacted with thionyl chloride (0.39 g, 0.0032787 mol), trimethylamine(0.36 g, 0.0035519 mol), and4-amino-5-iodo-2-(trifluoromethyl)benzonitrile (0.81 g, 0.0025956 mol)to afford the titled compound. The product was purified by a silica gelcolumn using DCM and ethyl acetate (9:1) as eluent to afford 0.80 g(64.6%) of the titled compound as a light brown solid.

¹H NMR (400 MHz, CDCl₃) δ 9.53 (s, 1H, NH), 8.92 (s, 1H, ArH), 8.24 (s,1H, ArH), 7.26 (s, 1H, OH), 4.04 (d, J=10.4 Hz, 1H, CH), 3.62 (d, J=10.4Hz, 1H, CH), 1.67 (s, 3H, CH₃).

Mass (ESI, Positive): 479.25[M+H]⁺.

(S)—N-(4-Cyano-2-iodo-5-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₁F₄IN₄O₂) (1052)

To a solution of 4-fluoro-1H-pyrazole (0.09 g, 0.001048 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.15g, 0.003669 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-2-iodo-5-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.50 g, 0.001048 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using hexanes and ethyl acetate (2:1 to 1:1) as eluentto afford 0.32 g (64%) of the titled compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.60 (s, 1H, NH), 8.76 (s, 1H, ArH), 8.69 (s,1H, ArH), 7.76 (d, J=4.8 Hz, 1H, Pyrazole-H), 7.36 (d, J=4.4 Hz, 1H,Pyrazole-H), 6.85 (s, 1H, OH), 4.39 (d, J=14.0 Hz, 1H, CH), 4.20 (d,J=14.0 Hz, 1H, CH), 1.41 (s, 3H, CH₃).

Mass (ESI, Negative): 481.00 [M−H]⁻;

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-(4-fluorophenyl)-1H-tetrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₉H₁₄F₄N₆O₂) (1053)

To a solution of 5-(4-fluorophenyl)-1H-tetrazole (0.20 g, 0.001219 mol)in anhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.17g, 0.004265 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.43 g, 0.001219 mol) was added to above solution, and the resultingreaction mixture was allowed to stir 2 days at room temperature underargon. The reaction was quenched by water and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (9:1) as eluent to afford0.053 g (10%) of the titled compound as a yellowish solid.

¹H NMR (400 MHz, CDCl₃) δ 10.39 (s, 1H, NH), 8.44 (s, 1H, ArH), 8.26 (d,J=8.2 Hz, 1H, ArH), 8.10 (d, J=8.2 Hz, 1H, ArH), 7.93-7.89 (m, 2H, ArH),7.30 (t, J=8.2 Hz, 2H, ArH), 6.64 (s, 1H, OH), 5.09 (d, J=14.0 Hz, 1H,CH), 4.92 (d, J=14.0 Hz, 1H, CH), 1.55 (s, 3H, CH₃).

Mass (ESI, Negative): 433.17 [M−H]⁻.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-methoxy-1H-pyrazol-1-yl)-2-methylpropanamide(C₁₆H₁₅F₃N₄O₃) (1054)

To a solution of 4-methoxy-1H-pyrazole (0.12 g, 0.001233 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.17g, 0.004281 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.43 g, 0.001233 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (9:1) as eluent to afford0.30 g (60%) of the titled compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H, NH), 8.46 (d, J=2.0 Hz, 1H,ArH), 8.24 (dd, J=8.2 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.2 Hz, 1H,ArH), 7.35 (d, J=0.8 Hz, 1H, Pyrazole-H), 7.15 (d, J=0.8 Hz, 1H,Pyrazole-H), 6.25 (s, 1H, OH), 4.35 (d, J=14.0 Hz, 1H, CH), 4.18 (d,J=14.0 Hz, 1H, CH), 3.61 (s, 3H, CH₃), 1.36 (s, 3H, CH₃).

HRMS [C₁₆H₁₆F₃N₄O₃ ⁺]: calcd 369.1175, found 369.1182[M+H]⁺. Purity:99.28% (HPLC).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-methyl-1H-pyrazol-1-yl)propanamide(C₁₆H₁₅F₃N₄O₂) (1055)

To a solution of 4-methyl-1H-pyrazole (0.10 g, 0.001218 mol) inanhydrous THF (5 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.17g, 0.004263 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.428 g, 0.001218 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (19:1) as eluent to afford0.28 g (66%) of the titled compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H, NH), 8.46 (d, J=2.0 Hz, 1H,ArH), 8.23 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.8 Hz, 1H,ArH), 7.41 (s, 1H, Pyrazole-H), 7.17 (s, 1H, Pyrazole-H), 6.24 (s, 1H,OH), 4.40 (d, J=14.0 Hz, 1H, CH), 4.22 (d, J=14.0 Hz, 1H, CH), 1.97 (s,3H, CH₃), 1.36 (s, 3H, CH₃).

HRMS [C₁₆H₁₆F₃N₄O₂ ⁺]: calcd 353.1225, found 353.1232[M+H]⁺. Purity:99.75% (HPLC).

N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(C₁₂H₉F₃N₂O₂) (1056)

2-Methyloxirane-2-carboxylic acid (1.00 g, 0.009892 mol) was reactedwith thionyl chloride (1.41 g, 0.011871 mol), trimethylamine (1.30 g,0.01286 mol), and 4-amino-2-(trifluoromethyl)benzonitrile (1.84 g,0.009892 mol) to afford the titled compound. The product was purified bya silica gel column using DCM and ethyl acetate (19:1) as eluent toafford 1.52 g (57%) of the titled compound as a yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H, NH), 8.55 (d, J=1.6-2.0 Hz,1H, ArH), 8.32 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.12 (d, J=8.8 Hz, 1H,ArH), 6.39 (s, 1H, OH), 3.94 (d, J=11.2 Hz, 1H, CH), 3.70 (d, J=11.2 Hz,1H, CH), 1.44 (s, 3H, CH₃).

Mass (ESI, Negative): [M−H]⁻; (ESI, Positive): [M+Na]⁺.

N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂F₄N₄O₂) (1057)

To a solution of 4-fluoro-pyrazole (0.10 g, 0.001162 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.14 g,0.003486 mol). After addition, the resulting mixture was stirred forthree hours.N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.31 g, 0.001162 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using hexanes and ethyl acetate (2:1 to 1:1) as eluent to afford0.37 g (90%) of the titled compound as a yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H, NH), 8.47 (d, J=2.0 Hz, 1H,ArH), 8.24 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.8 Hz, 1H,ArH), 7.74 (d, J=4.4 Hz, 1H, Pyrazole-H), 7.41 (d, J=4.0 Hz, 1H,Pyrazole-H), 6.31 (s, 1H, OH), 4.39 (d, J=14.0 Hz, 1H, CH), 4.21 (d,J=14.4 Hz, 1H, CH), 1.34 (s, 3H, CH₃).

Mass (ESI, Negative): [M−H]⁻; (ESI, Positive): [M+Na]⁺.

(S)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₂H₉F₃N₂O₂)

(S)-3-Bromo-2-hydroxy-2-methylpropanoic acid (1.00 g, 0.0054645 mol)reacted with thionyl chloride (0.78 g, 0.0065574 mol), trimethylamine(0.72 g, 0.0071038 mol), and 4-amino-2-(trifluoromethyl)benzonitrile(1.02 g, 0.0054645 mol) to afford the titled compound. The product waspurified by a silica gel column using DCM and ethyl acetate (19:1) aseluent to afford 1.75 g (90%) of the titled compound as a yellowishsolid.

Mass (ESI, Positive): 351.08 [M+Na]⁺.

(R)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₂F₄N₄O₂)

To a solution of 4-fluoro-pyrazole (0.10 g, 0.001162 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.16 g,0.0040665 mol). After addition, the resulting mixture was stirred forthree hours.(S)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.41 g, 0.001162 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using hexanes and ethyl acetate (2:1 to 1:1) as eluent to afford0.27 g (64%) of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H, NH), 8.47 (d, J=1.6-2.0 Hz,1H, ArH), 8.24 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H,ArH), 7.74 (d, J=4.4 Hz, 1H, Pyrazole-H), 7.41 (d, J=4.4 Hz, 1H,Pyrazole-H), 6.31 (s, 1H, OH), 4.39 (d, J=14.0 Hz, 1H, CH), 4.21 (d,J=14.4 Hz, 1H, CH), 1.34 (s, 3H, CH₃).

Mass (ESI, Positive): 357.11 [M+Na]⁺.

(S)-3-(4-Bromo-3-fluoro-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₅H₁₁BrF₄N₄O₂) (1058)

To a solution of 4-bromo-3-fluoro-1H-pyrazole (0.30 g, 0.001819 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.26g, 0.006365 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.64 g, 0.001819 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using ethyl acetate and hexanes (2:1) as eluent toafford 0.34 g (34%) of the titled compound as a pinkish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H, NH), 8.45 (d, J=2.0-1.6 Hz,1H, ArH), 8.23 (dd, J=8.2 Hz, J=2.0 Hz, 1H, ArH), 8.11 (d, J=8.2 Hz, 1H,ArH), 7.82 (d, J=2.0 Hz, 1H, Pyrazole-H), 6.35 (s, 1H, OH), 4.35 (d,J=14.0 Hz, 1H, CH), 4.04 (d, J=14.0 Hz, 1H, CH), 1.37 (s, 3H, CH₃).

HRMS [C₁₅H₁₂BrF₄N₄O₂ ⁺]: calcd 435.0080, found 435.0080[M+H]⁺. Purity:96.98% (HPLC).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(4-fluorophenyl)-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide(C₂₁H₁₅F₅N₄O₂) (1059)

The mixture of(S)-3-(4-bromo-3-fluoro-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.20 g, 0.4596 mmol), 4-fluoro boronic acid (77 mg, 0.5515 mmol),Pd(II)(OAc)₂ (2-3 mg, 0.009192 mmol), PPh₃ (7-8 mg, 0.02758 mmol), andK₂CO₃ (0.13 g, 0.965 mmol) in the mixture of ACN (4-5 mL) and H₂O (2-3mL) was degassed and refilled with argon three times. The resultingreacting mixture was heated at reflux for 3 hours under argon. Theproduct was purified by a silica gel column using hexanes and ethylacetate (2:1 to 1:1) as eluent to afford 51 mg (25%) of the titledcompound as a off-white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H, NH), 8.06 (d, J=1.6 Hz, 1H, ArH),7.85 (dd, J=8.2 Hz, J=1.6 Hz, 1H, ArH), 7.77 (d, J=8.2 Hz, 1H, ArH),7.51 (d, J=3.0 Hz, 1H, Pyrazole-H), 7.43-7.40 (m, 2H, ArH), 7.08-7.04(m, 2H, ArH), 4.57 (d, J=10.5 Hz, 1H, CH), 4.7 (d, J=10.5 Hz, 1H, CH),1.26 (s, 3H, CH₃).

HRMS [C₂₁H₁₆F₅N₄O₂ ⁺]: calcd 451.1193, found 451.1196[M+H]⁺. Purity: %(HPLC).

(S)-3-(3-Bromo-4-cyano-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₆H₁₁BrF₃N₅O₂) (1060)

To a solution of 3-bromo-4-cyano-1H-pyrazole (0.20 g, 0.0011629 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.163g, 0.00407 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.41 g, 0.0011629 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using ethyl acetate and hexanes (2:1) as eluent toafford 0.10 g (20%) of the titled compound as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H, NH), 8.40 (s 1H, Pyrazole-H),8.41 (s, 1H, ArH), 8.20 (d, J=8.4 Hz, 1H, ArH), 8.11 (d, J=8.4 Hz, 1H,ArH), 6.47 (s, 1H, OH), 4.52 (d, J=13.6 Hz, 1H, CH), 4.33 (d, J=13.6 Hz,1H, CH), 1.41 (s, 3H, CH₃).

HRMS [C₁₆H₁₂BrF₃N₅O₂ ⁺]: calcd 442.0126, found 442.0109[M+H]⁺. Purity:98.84% (HPLC).

(S)-3-(3-Chloro-4-methyl-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(C₁₆H₁₄ClF₃N₄O₂) (1061)

To a solution of 3-chloro-4-methyl-1H-pyrazole (0.15 g, 0.001287 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.18g, 0.0045045 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(0.45 g, 0.001287 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water and extracted with ethylacetate. The organic layer was washed with brine, dried with MgSO₄,filtered, and concentrated under vacuum. The product was purified by asilica gel column using DCM and ethyl acetate (98:2 to 95:5) as eluentto afford 0.27 g (54%) of the titled compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H, NH), 8.42 (d, J=0.8 Hz, 1H,ArH), 8.21 (dd, J=8.4 Hz, J=0.8 Hz, 1H, ArH), 8.10 (d, J=8.2 Hz, 1H,ArH), 7.50 (s 1H, Pyrazole-H), 6.29 (s, 1H, OH), 4.36 (d, J=14.4 Hz, 1H,CH), 4.18 (d, J=14.4 Hz, 1H, CH), 1.91 (s, 3H, CH₃), 1.35 (s, 3H, CH₃).

HRMS [C₁₆H₁₅ClF₃N₄O₂ ⁺]: calcd 387.0836, found 387.0839[M+H]⁺. Purity:97.07% (HPLC).

(S)-3-(4-Fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide(1062)

To a dry, nitrogen-purged 100 mL round-bottom flask equipped with adropping funnel under argon atmosphere, NaH of 60% dispersion in mineraloil (674 mg, 16.9 mmol) was added in 60 mL of anhydrous THF solvent inthe flask at ice-water bath, and 4-fluoro-1H-pyrazole (691 mg, 8.03mmol) was stirred in over 30 min at the ice-water bath. Into the flask,the solution of(R)-3-bromo-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide(2.98 g, 8.03 mmol) in 10 mL of anhydrous THF was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at room temperature. After adding 1 mL of H₂O, the reactionmixture was condensed under reduced pressure, and then dispersed into 50mL of EtOAc, washed with 50 mL (×2) water, evaporated, dried overanhydrous MgSO₄, and evaporated to dryness. The mixture was purifiedwith flash column chromatography as an eluent EtOAc/hexane=½ to producedesigned compound (2.01 g, 67%) as yellowish solid.

MS (ESI) m/z 375.08 [M−H]⁻; 377.22 [M+H]⁺; 399.04 [M+Na];

¹⁹F NMR (CDCl₃, decoupled) δ −60.13, −176.47; assigned by NOE and COSY;¹H NMR (400 MHz, CDCl₃) δ 9.14 (bs, 1H, NH), 8.01 (s, 1H), 7.97-7.91 (m,2H), 7.38 (d, J=3.6 Hz, 1H), 7.35 (d, J=4.4 Hz, 1H), 5.95 (s, 1H, OH),4.56 (d, J=14.0 Hz, 1H), 4.17 (d, J=14.0 Hz, 1H), 1.48 (s, 3H).

(S)-3-(4-Fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanoic acid(1062a)

To a solution of 1062 (1.886 g, 5.29 mmol) in EtOH (40 ml) and water (20ml) was added NaOH (424 mg, 10.59 mmol) and the reaction mixture washeated to reflux for 2 h, evaporated (to remove the EtOH) and thenextracted with EtOAc. The aqueous phase was acidified to pH 1 andextracted with EtOAc. The extract was dried over Na₂SO₄, filtered andevaporated to afford the title compound (845 mg, 85%) as a brown oil. MS(ESI) m/z 187.06 [M−H]⁻; 188.91 [M+H]⁺;

¹⁹F NMR (acetone-d₆, decoupled) δ-0.24; assigned by NOE and COSY.

¹H NMR (400 MHz, acetone-d₆) δ 7.66 (d, J=4.4 Hz, 1H), 7.36 (d, J=4.0Hz, 1H), 4.45 (d, J=14.0 Hz, 1H), 4.27 (d, J=14.0 Hz, 1H), 1.38 (s, 3H).¹³C NMR (100 MHz, acetone-d₆) δ 175.70, 150.36 (d, J=24.12 Hz), 126.53(d, J=13.6 Hz), 118.21 (d, J=28.0 Hz), 74.86, 60.59, 23.77.

Preparation of(S)—N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-2-methylpropanamide(1063)(S)-3-Azido-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide(1064)

A solution of(R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide(352 mg, 1 mmol) in 10 mL of DMF was treated with NaN₃ (325 mg, 5 mmol)under Ar at 80° C. for 24 h. The reaction mixture was then cooled andextracted with CH₂Cl₂ (3×20 mL). The combined organic layers were washedwith H₂O (3×20 mL) and brine, dried and evaporated to give a crude oil,which purified by silica gel chromatography (EtOAc/n-hexane=1:2, v/v) toafford product. Yield=87%;

MS (ESI) m/z 313.03 [M−H]⁻; ¹⁹F NMR (CDCl₃, decoupled) δ-62.11;

¹H NMR (400 MHz, CDCl₃) δ 9.16 (bs, 1H, NH), 8.89 (s, 1H), 8.77 (s, 1H),3.90 (d, J=12.0 Hz, 1H), 3.52 (d, J=12.0 Hz, 1H), 3.20 (bs, 1H, OH),1.55 (s, 3H).

(S)—N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxy-2-methylpropanamide(1063)

To a suspension of copper(I)iodide (11 mg, 0.055 mmoL) in acetonitrile(7 mL)/water (3 mL) mixture was added 1064 (57 mg, 0.182 mmol) at roomtemperature and then 1-ethynyl-4-fluorobenzene (0.015 mL, 0.182 mmol)was added. The resulting reaction mixture was stirred at roomtemperature for 3 days. The mixture was evaporated under reducedpressure, poured into water:brine (1:1) and then extracted with ethylacetate. The combined organic extracts were then washed with brine,dried over sodium sulphate, filtered and evaporated. Purification bychromatography (silica, 60% ethyl acetate in hexane) to afford theproduct as a yellow solid (51.3 mg, 65%).

MS (ESI) m/z 433.09 [M−H]⁻435.06 [M+H]⁺;

¹⁹F NMR (acetone-d₆, decoupled) δ 114.58, 61.66; assigned by NOE andCOSY;

¹H NMR (400 MHz, acetone-d₆) δ 10.16 (bs, 1H, NH), 9.28 (s, 1H), 8.88(s, 1H), 8.31 (s, 1H), 7.90 (t, J=7.8 Hz, 2H), 7.20 (t, J=8.8 Hz, 2H),5.73 (bs, 1H, OH), 4.94 (d, J=14.2 Hz, 1H), 4.73 (d, J=14.2 Hz, 1H),1.62 (s, 3H).

Example 14 SARDs Regressed CPRC VCaP Tumors

VCaP prostate cancer cells were implanted (in combination with matrigel(1:1 mix)) on the flanks subcutaneously in SRG rats (10 millioncells/rat). When the tumors reach 300-500 mm³, the animals werecastrated and the tumors were allowed to regrow as castration-resistantprostate cancer. When the tumors regrew, the animals were randomizedinto three groups, vehicle (15% DMSO+85% PEG-300), enzalutamide (30mg/kg/day), or compound 1002 (60 mg/kg/day). The animals were orallytreated and tumor volume and body weight were recorded thrice weekly.Tumor volume or percent change in tumor volume was calculated.

Vehicle-treated tumors grew robustly in castrated environment indicatingthat the tumors were castration-resistant, i.e., tumor were CRPC.Enzalutamide inhibited the growth of the tumors, while compound 1002regressed the tumors to undetectable levels (FIG. 35A). All individualanimals treated with 1002 had tumor volume reduced to unmeasurable by 22days (FIG. 35B), whereas enzalutamide response was more variable andincomplete even at 30 days.

Example 15 SARDs Inhibited Growth of Tumor and Caused Rapid TumorRegression in Anti-Androgen Resistant (MDVR) VCaP Cells in Intact andCastrated Animals

VCaP cells that have been rendered enzalutamide resistant were implanted(in combination with matrigel (1:1 mix)) on the flanks subcutaneously inSRG rats (10 million cells/rat). When the tumor reached 10,800 mm³, theanimal was treated orally with compound 1002 (60 mg/kg/day) to determineif the tumor growth is slowed. Tumor volume and body weight was recordedthrice weekly.

Animal No. 803 was cryptorchid and there were complications upon tryingto remove testes, so the animal was left intact. Before initiation of1002 treatments the MDV3100 (enzalutamide) resistant (MDVR) VCaP cellsgrew robustly, presumably supported by the endogenous androgens. 1002quickly inhibited growth and caused rapid tumor regression, however, theanimal was sacrificed due to loose stools (FIG. 36). Interestingly, theresponse to treatment in this animal was rapid despite the androgenreplete milieu of an intact rat. E.g., FIG. 36A demonstrates that as thetumor began to grow, the serum PSA levels began to rise as shown by thenumbers above each time point in the tumor volume graph (left panel inFIG. 36A), however, immediately after initiation of 1002 treatments thePSA levels fell to zero.

In the right panel of FIG. 36A, serum PSA levels are graphed (numberprovided on the graph are serum PSA values (ng/mL); blood was obtainedweekly and serum separated and stored for PSA analysis; tumor volume wasmeasured thrice weekly) for this animal allowing visualization of thedramatic rise in PSA with tumor growth and rapid PSA response uponinitiation around day 58. By comparison in FIG. 36B, vehicle treated andenzalutamide treated animal experienced rapid tumor volume increases.This is preliminary evidence that SARDs of this invention can overcomeenzalutamide resistance in the presence of androgens and that the rapidtumor response is based on blocking the AR-axis. This provided theinspiration to test MDVR xenografts in intact animals. The experimentwas repeated with three rats per group and the same result was observed.Rapid and robust tumor response in MDVR VCaP tumors in intact ratstreated with 1002 and rapid progression in enzalutamide and vehicletreated intact rats (FIG. 37). This is the first evidence that an ARantagonist can inhibit CRPC tumor growth in an intact animal species(rat). This result provide evidence that SARDs of this invention can beused to treat prostate cancer even in the presence of endogenous agonist(i.e., intact animals) which is an unexpected result and differs fromthe standard of care in which the first pharmacotherapy is typicallyandrogen-deprivation therapy. Although this result is in an enzalutamideresistant CPRC, it provides a basis for testing in early prostatecancers and suggests the possibility of adjuvant or neoadjuvant use ofSARDs of this invention in intact men.

MDVR VCaP Xenograft Growth in Castrated Rats:

MDVR VCaP prostate cancer cells were implanted (in combination withmatrigel (1:1 mix)) on the flanks subcutaneously in SRG rats (10 millioncells/rat). When the tumors reach 300-500 mm³, the animals werecastrated and the tumors were allowed to regrow as castration-resistantprostate cancer. When the tumors regrew, the animals were randomizedinto three groups, vehicle (15% DMSO+85% PEG-300), enzalutamide (30mg/kg/day), or compound 1002 (60 mg/kg/day). The animals were orallytreated and tumor volume and body weight were recorded thrice weekly.Tumor volume or percent change in tumor volume was calculated.

Vehicle-treated tumors grew robustly in castrated environment indicatingthat the tumors were castration-resistant, i.e., tumor were CRPC.Enzalutamide treated tumors also continued to grow almost comparably tovehicle, while compound 1002 regressed the tumors to inhibited tumorgrowth significantly (FIG. 38) with tumor at sacrifice (approximatelyday 26) slightly smaller than at initiation of treatment or ˜2000 mm³.By comparison, vehicle and enzalutamide tumor grew by from ˜2000 mm³ to˜6000 mm³ or ˜200% increased tumor volume. This demonstrated that SARDsof this invention are able to treat antiandrogen resistant castrationresistant prostate cancer (MDVR VCaP) which over expresses CYP17A1 suchthat there is intratumoral androgen synthesis as well. Correspondingly,SARDs of this invention are expected to be able to treat CRPC (andpossibly CSPC) including patients that have failed enzalutamide orapalutamide and possibly abiraterone treatments, or patientsoverexpressing CYP17A1 or AKR1C3.

Example 16 X-Linked Spinal-Bulbar Muscular Atrophy (SBMA) Method

Transgenic mice that express AR121Q (121 polyglutamine repeats insteadof the usual 15-24 repeats) will be treated with vehicle or SARD orally.One group of mice will be castrated to serve as positive control ascirculating androgens will worsen the SBMA condition. Body weight,composition, and grip strength will be measured before the initiation ofthe experiment. Animals will be treated and weekly measurements will beperformed. Animals will be treated and monitored until they die. AR121Qmice lives only up to 60-80 days and hence evaluating the survival inthe presence of SARD treatment is possible.

Example 17 ALS Method

All experiments will be performed in male hSOD1-G93A mice (Jax labs;PMID: 26786249) as a model of anterior lateral sclerosis (ALS). Micewill be randomized and treated with either vehicle or SARD of thisinvention dissolved in DMSO+PEG-300 (15%+85%). Simultaneously, a groupof mice will be castrated and used as positive control as castration hasbeen shown to extend survival and disease duration in this model (PMID:24630363). Mice will be treated orally every day until they reachmorbidity. Weekly body weight and composition by magnetic resonanceimaging (MRI) will be recorded. The mice performance will be measuredeach week by using a grip strength meter (Columbus instruments) orrotarod. Inability for the mice to move will be considered as a terminaldisease state and the mice will be sacrificed.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

What is claimed is:
 1. A method of treating prostate cancer in a subject in need thereof, wherein said subject has AR overexpressing prostate cancer, castration-resistant prostate cancer, castration-sensitive prostate cancer, AR-V7 expressing prostate cancer, or d567ES expressing prostate cancer, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I

wherein T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; X is CH or N; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; A is R² or R³; R² is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q¹, Q², Q³ and Q⁴, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof; wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring.
 2. The method of claim 1, wherein said SARD compound is represented by the structure of formula IA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 3. The method of claim 1, wherein said SARD compound is represented by the structure of formula IB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 4. The method of claim 1, wherein said SARD compound is represented by the structure of formula II:

wherein T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; X is CH or N; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; A is R² or R³ R² is a pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole, imidazole, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q¹, Q², Q³ and Q⁴, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof; wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring.
 5. The method of claim 4, wherein said SARD compound is represented by the structure of formula IIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 6. The method of claim 4, wherein said SARD compound is represented by the structure of formula IIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 7. The method of claim 1, wherein said SARD compound is represented by the structure of formula VII:

wherein X is CH or N; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and Q², Q³ and Q⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 8. The method of claim 7, wherein said SARD compound is represented by the structure of formula VIIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 9. The method of claim 7, wherein said SARD compound is represented by the structure of formula VIIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 10. The method of claim 1, wherein Q¹, Q², Q³ and Q⁴ is hydrogen, CN, NO₂, CF₃, F, Cl, Br, I, NHCOOR, N(R)₂, NHCOR, COR, or substituted or unsubstituted phenyl.
 11. The method of claim 1, wherein said SARD compound is represented by the structure of any one of the following compounds:


11. The method of claim 1, wherein said castration-resistant prostate cancer is AR overexpressing castration-resistant prostate cancer, F876L mutation expressing castration-resistant prostate cancer, F876L_T877A double mutation expressing castration-resistant prostate cancer, AR-V7 expressing castration-resistant prostate cancer, d567ES expressing castration-resistant prostate cancer, and/or castration-resistant prostate cancer characterized by intratumoral androgen synthesis.
 12. The method of claim 1, wherein said castration-sensitive prostate cancer is F876L mutation expressing castration-sensitive prostate cancer, F876L_T877A double mutation castration-sensitive prostate cancer, and/or castration-sensitive prostate cancer characterized by intratumoral androgen synthesis.
 13. The method of claim 1, wherein said treating of castration-sensitive prostate cancer is conducted in a non-castrate setting, or as monotherapy, or when castration-sensitive prostate cancer tumor is resistance to enzalutamide, apalutamide, and/or abiraterone.
 14. A method of treating breast cancer in a subject in need thereof, wherein said subject has AR expressing breast cancer, AR-SV expressing breast cancer, and/or AR-V7 expressing breast cancer, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; X is CH or N; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; A is R² or R³; R² is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q¹, Q², Q³ and Q⁴, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof; wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring.
 15. The method of claim 14, wherein said SARD compound is represented by the structure of formula IA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 16. The method of claim 14, wherein said SARD compound is represented by the structure of formula IB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 17. The method of claim 14, wherein said SARD compound is represented by the structure of formula II:

wherein T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; X is CH or N; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; A is R² or R³ R² is a pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole, imidazole, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q¹, Q², Q³ and Q⁴, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof; wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring.
 18. The method of claim 17, wherein said SARD compound is represented by the structure of formula IIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 19. The method of claim 17, wherein said SARD compound is represented by the structure of formula IIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 20. The method of claim 14, wherein said SARD compound is represented by the structure of formula VII:

wherein X is CH or N; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and Q², Q³ and Q⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 21. The method of claim 20, wherein said SARD compound is represented by the structure of formula VIIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 22. The method of claim 20, wherein said SARD compound is represented by the structure of formula VIIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 23. The method of claim 14, wherein Q¹, Q², Q³ and Q⁴ is hydrogen, CN, NO₂, CF₃, F, Cl, Br, I, NHCOOR, N(R)₂, NHCOR, COR, or substituted or unsubstituted phenyl.
 24. The method of claim 14, wherein said SARD compound is represented by the structure of any one of the following compounds:


25. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of a hormonal condition in a male in need thereof, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; X is CH or N; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; A is R² or R³; R² is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q¹, Q², Q³ and Q⁴, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof; wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring.
 26. The method of claim 25, wherein said SARD compound is represented by the structure of formula IA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 27. The method of claim 25, wherein said SARD compound is represented by the structure of formula IB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 28. The method of claim 25, wherein said SARD compound is represented by the structure of formula II:

wherein T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; X is CH or N; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; A is R² or R³ R² is a pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole, imidazole, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q¹, Q², Q³ and Q⁴, each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; R³ is NHR², halide, N₃, OR⁴, CF₃, COR⁴, COCl, COOCOR⁴, COOR⁴, OCOR⁴, OCONHR⁴, NHCOOR⁴, NHCONHR⁴, OCOOR⁴, CN, CONH₂, CONH(R⁴), CON(R⁴)₂, SR⁴, SO₂R⁴, SOR⁴ SO₃H, SO₂NH₂, SO₂NH(R⁴), SO₂N(R⁴)₂, NH₂, NH(R⁴), N(R⁴)₂, CO(N-heterocycle), NO₂, cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH)₂ or OPO(OH)₂; and R⁴ is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof; wherein if A is Br or I, R¹ is CH₃, and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring.
 29. The method of claim 28, wherein said SARD compound is represented by the structure of formula IIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 30. The method of claim 28, wherein said SARD compound is represented by the structure of formula IIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 31. The method of claim 25, wherein said SARD compound is represented by the structure of formula VII:

wherein X is CH or N; Y is H, CF₃, F, I, Br, Cl, CN, or C(R)₃; Z is H, NO₂, CN, halide, COOH, COR, NHCOR, CONHR, or Y and Z form a 5 to 8 membered fused ring; R¹ is H, CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; T is H, OH, OR, OCOR, CH₃, —NHCOCH₃, or NHCOR; or T and R¹ form a 3-8 carbocyclic or heterocyclic ring; R is H, alkyl, alkenyl, haloalkyl, alcohol, CH₂CH₂OH, CF₃, CH₂Cl, CH₂CH₂Cl, aryl, F, Cl, Br, I, or OH; and Q², Q³ and Q⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF₃, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO₂, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)₂, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 32. The method of claim 31, wherein said SARD compound is represented by the structure of formula VIIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 33. The method of claim 31, wherein said SARD compound is represented by the structure of formula VIIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.
 34. The method of claim 25, wherein Q¹, Q², Q³ and Q⁴ is hydrogen, CN, NO₂, CF₃, F, Cl, Br, I, NHCOOR, N(R)₂, NHCOR, COR, or substituted or unsubstituted phenyl.
 35. The method of claim 25, wherein said SARD compound is represented by the structure of any one of the following compounds:


36. The method of claim 25, wherein said condition is hypergonadism, hypersexuality, sexual dysfunction, gynecomastia, precocious puberty in a male, alterations in cognition and mood, depression, hair loss, hyperandrogenic dermatological disorders, pre-cancerous lesions of the prostate, benign prostate hyperplasia, prostate cancer and/or other androgen-dependent cancers. 